DNA Repair

DNA repair
DNA repair is a collection of processes by

which a cell identifies and corrects
damage to the DNA molecules that
encode its genome.[1] In human cells, both
normal metabolic activities and
environmental factors such as radiation
can cause DNA damage, resulting in tens
of thousands of individual molecular
lesions per cell per day.[2] Many of these
lesions cause structural damage to the
DNA molecule and can alter or eliminate
the cell's ability to transcribe the gene that
the affected DNA encodes. Other lesions
induce potentially harmful mutations in the
cell's genome, which affect the survival of
its daughter cells after it undergoes
mitosis. As a consequence, the DNA repair
process is constantly active as it responds
to damage in the DNA structure. When
normal repair processes fail, and when
cellular apoptosis does not occur,
irreparable DNA damage may occur,
including double-strand breaks and DNA
crosslinkages (interstrand crosslinks or
ICLs).[3][4] This can eventually lead to
malignant tumors, or cancer as per the two
hit hypothesis.
DNA damage resulting in multiple broken chromosomes
The rate of DNA repair is dependent on

many factors, including the cell type, the
age of the cell, and the extracellular
environment. A cell that has accumulated
a large amount of DNA damage, or one
that no longer effectively repairs damage
incurred to its DNA, can enter one of three
possible states:
1. an irreversible state of dormancy,

known as senescence
2. cell suicide, also known as apoptosis
or programmed cell death
3. unregulated cell division, which can
lead to the formation of a tumor that
is cancerous
The DNA repair ability of a cell is vital to

the integrity of its genome and thus to the
normal functionality of that organism.
Many genes that were initially shown to
influence life span have turned out to be
involved in DNA damage repair and
protection.[5]
Paul Modrich talks about himself and his work in DNA repair.
The 2015 Nobel Prize in Chemistry was

awarded to Tomas Lindahl, Paul Modrich,
and Aziz Sancar for their work on the
molecular mechanisms of DNA repair
processes.[6][7]
DNA damage
DNA damage, due to environmental
factors and normal metabolic processes
inside the cell, occurs at a rate of 10,000
to 1,000,000 molecular lesions per cell per
day.[2] While this constitutes only
0.000165% of the human genome's
approximately 6 billion bases, unrepaired
lesions in critical genes (such as tumor
suppressor genes) can impede a cell's
ability to carry out its function and
appreciably increase the likelihood of
tumor formation and contribute to tumour
heterogeneity.
The vast majority of DNA damage affects

the primary structure of the double helix;
that is, the bases themselves are
chemically modified. These modifications
can in turn disrupt the molecules' regular
helical structure by introducing non-native
chemical bonds or bulky adducts that do
not fit in the standard double helix. Unlike
proteins and RNA, DNA usually lacks
tertiary structure and therefore damage or
disturbance does not occur at that level.
DNA is, however, supercoiled and wound
around "packaging" proteins called
histones (in eukaryotes), and both
superstructures are vulnerable to the
effects of DNA damage.
Sources
DNA damage can be subdivided into two

main types:
1. endogenous damage such as attack

by reactive oxygen species produced
from normal metabolic byproducts
(spontaneous mutation), especially
the process of oxidative deamination
1. also includes replication
errors
2. exogenous damage caused by
external agents such as
1. ultraviolet [UV 200–400 nm]
radiation from the sun or other
artificial light sources
2. other radiation frequencies,
including x-rays and gamma
rays
3. hydrolysis or thermal
disruption
4. certain plant toxins
5. human-made mutagenic
chemicals, especially
aromatic compounds that act
as DNA intercalating agents
6. viruses[8]
The replication of damaged DNA before

cell division can lead to the incorporation
of wrong bases opposite damaged ones.
Daughter cells that inherit these wrong
bases carry mutations from which the
original DNA sequence is unrecoverable
(except in the rare case of a back
mutation, for example, through gene
conversion).
Types
There are several types of damage to DNA

due to endogenous cellular processes:
1. oxidation of bases [e.g. 8-oxo-7,8-

dihydroguanine (8-oxoG)] and
generation of DNA strand
interruptions from reactive oxygen
species,
2. alkylation of bases (usually
methylation), such as formation of 7-
methylguanosine, 1-methyladenine, 6-
O-Methylguanine
3. hydrolysis of bases, such as
deamination, depurination, and
depyrimidination.
4. "bulky adduct formation" (e.g.,
benzo[a]pyrene diol epoxide-dG
adduct, aristolactam I-dA adduct)
5. mismatch of bases, due to errors in
DNA replication, in which the wrong
DNA base is stitched into place in a
newly forming DNA strand, or a DNA
base is skipped over or mistakenly
inserted.
6. Monoadduct damage cause by
change in single nitrogenous base of
DNA
7. Diadduct damage
Damage caused by exogenous agents

comes in many forms. Some examples
are:
1. UV-B light causes crosslinking

between adjacent cytosine and
thymine bases creating pyrimidine
dimers. This is called direct DNA
damage.
2. UV-A light creates mostly free
radicals. The damage caused by free
radicals is called indirect DNA
damage.
3. Ionizing radiation such as that
created by radioactive decay or in
cosmic rays causes breaks in DNA
strands. Intermediate-level ionizing
radiation may induce irreparable DNA
damage (leading to replicational and
transcriptional errors needed for
neoplasia or may trigger viral
interactions) leading to pre-mature
aging and cancer.
4. Thermal disruption at elevated
temperature increases the rate of
depurination (loss of purine bases
from the DNA backbone) and single-
strand breaks. For example,
hydrolytic depurination is seen in the
thermophilic bacteria, which grow in
hot springs at 40–80 °C.[9][10] The rate
of depurination (300 purine residues
per genome per generation) is too
high in these species to be repaired
by normal repair machinery, hence a
possibility of an adaptive response
cannot be ruled out.
5. Industrial chemicals such as vinyl
chloride and hydrogen peroxide, and
environmental chemicals such as
polycyclic aromatic hydrocarbons
found in smoke, soot and tar create a
huge diversity of DNA adducts-
ethenobases, oxidized bases,
alkylated phosphotriesters and
crosslinking of DNA, just to name a
few.
UV damage, alkylation/methylation, X-ray

damage and oxidative damage are
examples of induced damage.
Spontaneous damage can include the loss
of a base, deamination, sugar ring
puckering and tautomeric shift.
Constitutive (spontaneous) DNA damage
caused by endogenous oxidants can be
detected as a low level of histone H2AX
phosphorylation in untreated cells.[11]
Nuclear versus mitochondrial
In human cells, and eukaryotic cells in

general, DNA is found in two cellular
locations – inside the nucleus and inside
the mitochondria. Nuclear DNA (nDNA)
exists as chromatin during non-replicative
stages of the cell cycle and is condensed
into aggregate structures known as
chromosomes during cell division. In either
state the DNA is highly compacted and
wound up around bead-like proteins called
histones. Whenever a cell needs to
express the genetic information encoded
in its nDNA the required chromosomal
region is unravelled, genes located therein
are expressed, and then the region is
condensed back to its resting
conformation. Mitochondrial DNA
(mtDNA) is located inside mitochondria
organelles, exists in multiple copies, and is
also tightly associated with a number of
proteins to form a complex known as the
nucleoid. Inside mitochondria, reactive
oxygen species (ROS), or free radicals,
byproducts of the constant production of
adenosine triphosphate (ATP) via oxidative
phosphorylation, create a highly oxidative
environment that is known to damage
mtDNA. A critical enzyme in counteracting
the toxicity of these species is superoxide
dismutase, which is present in both the
mitochondria and cytoplasm of eukaryotic
cells.
Senescence and apoptosis
Senescence, an irreversible process in

which the cell no longer divides, is a
protective response to the shortening of
the chromosome ends, called telomeres.
The telomeres are long regions of
repetitive noncoding DNA that cap
chromosomes and undergo partial
degradation each time a cell undergoes
division (see Hayflick limit).[12] In contrast,
quiescence is a reversible state of cellular
dormancy that is unrelated to genome
damage (see cell cycle). Senescence in
cells may serve as a functional alternative
to apoptosis in cases where the physical
presence of a cell for spatial reasons is
required by the organism,[13] which serves
as a "last resort" mechanism to prevent a
cell with damaged DNA from replicating
inappropriately in the absence of pro-
growth cellular signaling. Unregulated cell
division can lead to the formation of a
tumor (see cancer), which is potentially
lethal to an organism. Therefore, the
induction of senescence and apoptosis is
considered to be part of a strategy of
protection against cancer.[14]
Mutation
It is important to distinguish between DNA

damage and mutation, the two major types
of error in DNA. DNA damage and
mutation are fundamentally different.
Damage results in physical abnormalities
in the DNA, such as single- and double-
strand breaks, 8-hydroxydeoxyguanosine
residues, and polycyclic aromatic
hydrocarbon adducts. DNA damage can
be recognized by enzymes, and thus can
be correctly repaired if redundant
information, such as the undamaged
sequence in the complementary DNA
strand or in a homologous chromosome, is
available for copying. If a cell retains DNA
damage, transcription of a gene can be
prevented, and thus translation into a
protein will also be blocked. Replication
may also be blocked or the cell may die.
In contrast to DNA damage, a mutation is

a change in the base sequence of the DNA.
A mutation cannot be recognized by
enzymes once the base change is present
in both DNA strands, and thus a mutation
cannot be repaired. At the cellular level,
mutations can cause alterations in protein
function and regulation. Mutations are
replicated when the cell replicates. In a
population of cells, mutant cells will
increase or decrease in frequency
according to the effects of the mutation on
the ability of the cell to survive and
reproduce.
Although distinctly different from each

other, DNA damage and mutation are
related because DNA damage often
causes errors of DNA synthesis during
replication or repair; these errors are a
major source of mutation.
Given these properties of DNA damage

and mutation, it can be seen that DNA
damage is a special problem in non-
dividing or slowly-dividing cells, where
unrepaired damage will tend to
accumulate over time. On the other hand,
in rapidly dividing cells, unrepaired DNA
damage that does not kill the cell by
blocking replication will tend to cause
replication errors and thus mutation. The
great majority of mutations that are not
neutral in their effect are deleterious to a
cell's survival. Thus, in a population of
cells composing a tissue with replicating
cells, mutant cells will tend to be lost.
However, infrequent mutations that provide
a survival advantage will tend to clonally
expand at the expense of neighboring cells
in the tissue. This advantage to the cell is
disadvantageous to the whole organism
because such mutant cells can give rise to
cancer. Thus, DNA damage in frequently
dividing cells, because it gives rise to
mutations, is a prominent cause of cancer.
In contrast, DNA damage in infrequently-
dividing cells is likely a prominent cause of
aging.[15]
Mechanisms
Cells cannot function if DNA damage
corrupts the integrity and accessibility of
essential information in the genome (but
cells remain superficially functional when
non-essential genes are missing or
damaged). Depending on the type of
damage inflicted on the DNA's double
helical structure, a variety of repair
strategies have evolved to restore lost
information. If possible, cells use the
unmodified complementary strand of the
DNA or the sister chromatid as a template
to recover the original information. Without
access to a template, cells use an error-
prone recovery mechanism known as
translesion synthesis as a last resort.
Damage to DNA alters the spatial

configuration of the helix, and such
alterations can be detected by the cell.
Once damage is localized, specific DNA
repair molecules bind at or near the site of
damage, inducing other molecules to bind
and form a complex that enables the
actual repair to take place.
Direct reversal
Cells are known to eliminate three types of

damage to their DNA by chemically
reversing it. These mechanisms do not
require a template, since the types of
damage they counteract can occur in only
one of the four bases. Such direct reversal
mechanisms are specific to the type of
damage incurred and do not involve
breakage of the phosphodiester backbone.
The formation of pyrimidine dimers upon
irradiation with UV light results in an
abnormal covalent bond between adjacent
pyrimidine bases. The photoreactivation
process directly reverses this damage by
the action of the enzyme photolyase,
whose activation is obligately dependent
on energy absorbed from blue/UV light
(300–500 nm wavelength) to promote
catalysis.[16] Photolyase, an old enzyme
present in bacteria, fungi, and most
animals no longer functions in humans,[17]
who instead use nucleotide excision repair
to repair damage from UV irradiation.
Another type of damage, methylation of
guanine bases, is directly reversed by the
enzyme methyl guanine methyl transferase
(MGMT), the bacterial equivalent of which
is called ogt. This is an expensive process
because each MGMT molecule can be
used only once; that is, the reaction is
stoichiometric rather than catalytic.[18] A
generalized response to methylating
agents in bacteria is known as the
adaptive response and confers a level of
resistance to alkylating agents upon
sustained exposure by upregulation of
alkylation repair enzymes.[19] The third
type of DNA damage reversed by cells is
certain methylation of the bases cytosine
and adenine.
Single-strand damage
Structure of the base-excision repair enzyme uracil-DNA glycosylase excising a hydrolytically-produced uracil residue
from DNA. The uracil residue is shown in yellow.
When only one of the two strands of a
double helix has a defect, the other strand
can be used as a template to guide the
correction of the damaged strand. In order
to repair damage to one of the two paired
molecules of DNA, there exist a number of
excision repair mechanisms that remove
the damaged nucleotide and replace it
with an undamaged nucleotide
complementary to that found in the
undamaged DNA strand.[18]
1. Base excision repair (BER): damaged

single bases or nucleotides are most
commonly repaired by removing the
base or the nucleotide involved and
then inserting the correct base or
nucleotide. In base excision repair, a
glycosylase[20] enzyme removes the
damaged base from the DNA by
cleaving the bond between the base
and the deoxyribose. These enzymes
remove a single base to create an
apurinic or apyrimidinic site (AP
site).[20] Enzymes called AP
endonucleases nick the damaged
DNA backbone at the AP site. DNA
polymerase then removes the
damaged region using its 5’ to 3’
exonuclease activity and correctly
synthesizes the new strand using the
complementary strand as a
template.[20] The gap is then sealed
by enzyme DNA ligase.[21]
2. Nucleotide excision repair (NER):
bulky, helix-distorting damage, such
as pyrimidine dimerization caused by
UV light is usually repaired by a three-
step process. First the damage is
recognized, then 12-24 nucleotide-
long strands of DNA are removed
both upstream and downstream of
the damage site by endonucleases,
and the removed DNA region is then
resynthesized.[22] NER is a highly
evolutionarily conserved repair
mechanism and is used in nearly all
eukaryotic and prokaryotic cells.[22] In
prokaryotes, NER is mediated by Uvr
proteins.[22] In eukaryotes, many more
proteins are involved, although the
general strategy is the same.[22]
3. Mismatch repair systems are present
in essentially all cells to correct
errors that are not corrected by
proofreading. These systems consist
of at least two proteins. One detects
the mismatch, and the other recruits
an endonuclease that cleaves the
newly synthesized DNA strand close
to the region of damage. In E. coli ,
the proteins involved are the Mut
class proteins: MutS, MutL, and
MutH. In most Eukaryotes, the analog
for MutS is MSH and the analog for
MutL is MLH. MutH is only present in
bacteria. This is followed by removal
of damaged region by an
exonuclease, resynthesis by DNA
polymerase, and nick sealing by DNA
ligase.[23]
Double-strand breaks
The main double-strand break repair pathways

Double-strand breaks, in which both
strands in the double helix are severed, are
particularly hazardous to the cell because
they can lead to genome rearrangements.
In fact, when a double-strand break is
accompanied by a cross-linkage joining
the two strands at the same point, neither
strand can be used as a template for the
repair mechanisms, so that the cell will not
be able to complete mitosis when it next
divides, and will either die or, in rare cases,
undergo a mutation.[3][4] Three
mechanisms exist to repair double-strand
breaks (DSBs): non-homologous end
joining (NHEJ), microhomology-mediated
end joining (MMEJ), and homologous
recombination (HR):[18][24]
DNA ligase, shown above repairing chromosomal damage, is an enzyme that joins broken nucleotides together by
catalyzing the formation of an internucleotide ester bond between the phosphate backbone and the deoxyribose
nucleotides.
1. In NHEJ, DNA Ligase IV, a specialized

DNA ligase that forms a complex
with the cofactor XRCC4, directly
joins the two ends.[25] To guide
accurate repair, NHEJ relies on short
homologous sequences called
microhomologies present on the
single-stranded tails of the DNA ends
to be joined. If these overhangs are
compatible, repair is usually
accurate.[26][27][28][29] NHEJ can also
introduce mutations during repair.
Loss of damaged nucleotides at the
break site can lead to deletions, and
joining of nonmatching termini forms
insertions or translocations. NHEJ is
especially important before the cell
has replicated its DNA, since there is
no template available for repair by
homologous recombination. There
are "backup" NHEJ pathways in higher
eukaryotes.[30] Besides its role as a
genome caretaker, NHEJ is required
for joining hairpin-capped double-
strand breaks induced during V(D)J
recombination, the process that
generates diversity in B-cell and T-cell
receptors in the vertebrate immune
system.[31]
2. MMEJ starts with short-range end
resection by MRE11 nuclease on
either side of a double-strand break
to reveal microhomology regions.[32]
In further steps,[33] Poly (ADP-ribose)
polymerase 1 (PARP1) is required and
may be an early step in MMEJ. There
is pairing of microhomology regions
followed by recruitment of flap
structure-specific endonuclease 1
(FEN1) to remove overhanging flaps.
This is followed by recruitment of
XRCC1–LIG3 to the site for ligating
the DNA ends, leading to an intact
DNA. MMEJ is always accompanied
by a deletion, so that MMEJ is a
mutagenic pathway for DNA repair.[34]
3. HR requires the presence of an
identical or nearly identical sequence
to be used as a template for repair of
the break. The enzymatic machinery
responsible for this repair process is
nearly identical to the machinery
responsible for chromosomal
crossover during meiosis. This
pathway allows a damaged
chromosome to be repaired using a
sister chromatid (available in G2 after
DNA replication) or a homologous
chromosome as a template. DSBs
caused by the replication machinery
attempting to synthesize across a
single-strand break or unrepaired
lesion cause collapse of the
replication fork and are typically
repaired by recombination.
In an in vitro system, MMEJ occurred in
mammalian cells at the levels of 10–20%
of HR when both HR and NHEJ
mechanisms were also available.[32]
The extremophile Deinococcus

radiodurans has a remarkable ability to
survive DNA damage from ionizing
radiation and other sources. At least two
copies of the genome, with random DNA
breaks, can form DNA fragments through
annealing. Partially overlapping fragments
are then used for synthesis of homologous
regions through a moving D-loop that can
continue extension until complementary
partner strands are found. In the final step,
there is crossover by means of RecA-
dependent homologous recombination.[35]
Topoisomerases introduce both single-

and double-strand breaks in the course of
changing the DNA's state of supercoiling,
which is especially common in regions
near an open replication fork. Such breaks
are not considered DNA damage because
they are a natural intermediate in the
topoisomerase biochemical mechanism
and are immediately repaired by the
enzymes that created them.
Another type of DNA double-strand breaks

originates from the DNA heat-sensitive or
heat-labile sites. These DNA sites are not
initial DSBs. However, they convert to DSB
after treating with elevated temperature.
Ionizing irradiation can induces a highly
complex form of DNA damage as
clustered damage. It consists of different
types of DNA lesions in various locations
of the DNA helix. Some of these closely
located lesions can probably convert to
DSB by exposure to high temperatures. But
the exact nature of these lesions and their
interactions is not yet known[36]
Translesion synthesis
Translesion synthesis (TLS) is a DNA
damage tolerance process that allows the
DNA replication machinery to replicate
past DNA lesions such as thymine dimers
or AP sites.[37] It involves switching out
regular DNA polymerases for specialized
translesion polymerases (i.e. DNA
polymerase IV or V, from the Y Polymerase
family), often with larger active sites that
can facilitate the insertion of bases
opposite damaged nucleotides. The
polymerase switching is thought to be
mediated by, among other factors, the
post-translational modification of the
replication processivity factor PCNA.
Translesion synthesis polymerases often
have low fidelity (high propensity to insert
wrong bases) on undamaged templates
relative to regular polymerases. However,
many are extremely efficient at inserting
correct bases opposite specific types of
damage. For example, Pol η mediates
error-free bypass of lesions induced by UV
irradiation, whereas Pol ι introduces
mutations at these sites. Pol η is known to
add the first adenine across the T^T
photodimer using Watson-Crick base
pairing and the second adenine will be
added in its syn conformation using
Hoogsteen base pairing. From a cellular
perspective, risking the introduction of
point mutations during translesion
synthesis may be preferable to resorting to
more drastic mechanisms of DNA repair,
which may cause gross chromosomal
aberrations or cell death. In short, the
process involves specialized polymerases
either bypassing or repairing lesions at
locations of stalled DNA replication. For
example, Human DNA polymerase eta can
bypass complex DNA lesions like guanine-
thymine intra-strand crosslink, G[8,5-Me]T,
although it can cause targeted and semi-
targeted mutations.[38] Paromita
Raychaudhury and Ashis Basu[39] studied
the toxicity and mutagenesis of the same
lesion in Escherichia coli by replicating a
G[8,5-Me]T-modified plasmid in E. coli with
specific DNA polymerase knockouts.
Viability was very low in a strain lacking
pol II, pol IV, and pol V, the three SOS-
inducible DNA polymerases, indicating that
translesion synthesis is conducted
primarily by these specialized DNA
polymerases. A bypass platform is
provided to these polymerases by
Proliferating cell nuclear antigen (PCNA).
Under normal circumstances, PCNA bound
to polymerases replicates the DNA. At a
site of lesion, PCNA is ubiquitinated, or
modified, by the RAD6/RAD18 proteins to
provide a platform for the specialized
polymerases to bypass the lesion and
resume DNA replication.[40][41] After
translesion synthesis, extension is
required. This extension can be carried out
by a replicative polymerase if the TLS is
error-free, as in the case of Pol η, yet if
TLS results in a mismatch, a specialized
polymerase is needed to extend it; Pol ζ.
Pol ζ is unique in that it can extend
terminal mismatches, whereas more
processive polymerases cannot. So when
a lesion is encountered, the replication fork
will stall, PCNA will switch from a
processive polymerase to a TLS
polymerase such as Pol ι to fix the lesion,
then PCNA may switch to Pol ζ to extend
the mismatch, and last PCNA will switch to
the processive polymerase to continue
replication.
Global response to DNA

damage
Cells exposed to ionizing radiation,
ultraviolet light or chemicals are prone to
acquire multiple sites of bulky DNA lesions
and double-strand breaks. Moreover, DNA
damaging agents can damage other
biomolecules such as proteins,
carbohydrates, lipids, and RNA. The
accumulation of damage, to be specific,
double-strand breaks or adducts stalling
the replication forks, are among known
stimulation signals for a global response
to DNA damage.[42] The global response
to damage is an act directed toward the
cells' own preservation and triggers
multiple pathways of macromolecular
repair, lesion bypass, tolerance, or
apoptosis. The common features of global
response are induction of multiple genes,
cell cycle arrest, and inhibition of cell
division.
Initial steps
The packaging of eukaryotic DNA into

chromatin presents a barrier to all DNA-
based processes that require recruitment
of enzymes to their sites of action. To
allow DNA repair, the chromatin must be
remodeled. In eukaryotes, ATP dependent
chromatin remodeling complexes and
histone-modifying enzymes are two
predominant factors employed to
accomplish this remodeling process.[43]
Chromatin relaxation occurs rapidly at the

site of a DNA damage.[44][45] In one of the
earliest steps, the stress-activated protein
kinase, c-Jun N-terminal kinase (JNK),
phosphorylates SIRT6 on serine 10 in
response to double-strand breaks or other
DNA damage.[46] This post-translational
modification facilitates the mobilization of
SIRT6 to DNA damage sites, and is
required for efficient recruitment of poly
(ADP-ribose) polymerase 1 (PARP1) to
DNA break sites and for efficient repair of
DSBs.[46] PARP1 protein starts to appear at
DNA damage sites in less than a second,
with half maximum accumulation within
1.6 seconds after the damage occurs.[47]
PARP1 synthesizes polymeric adenosine
diphosphate ribose (poly (ADP-ribose) or
PAR) chains on itself. Next the chromatin
remodeler ALC1 quickly attaches to the
product of PARP1 action, a poly-ADP
ribose chain, and ALC1 completes arrival
at the DNA damage within 10 seconds of
the occurrence of the damage.[45] About
half of the maximum chromatin relaxation,
presumably due to action of ALC1, occurs
by 10 seconds.[45] This then allows
recruitment of the DNA repair enzyme
MRE11, to initiate DNA repair, within 13
seconds.[47]
γH2AX, the phosphorylated form of H2AX

is also involved in the early steps leading
to chromatin decondensation after DNA
double-strand breaks. The histone variant
H2AX constitutes about 10% of the H2A
histones in human chromatin.[48] γH2AX
(H2AX phosphorylated on serine 139) can
be detected as soon as 20 seconds after
irradiation of cells (with DNA double-
strand break formation), and half
maximum accumulation of γH2AX occurs
in one minute.[48] The extent of chromatin
with phosphorylated γH2AX is about two
million base pairs at the site of a DNA
double-strand break.[48] γH2AX does not,
itself, cause chromatin decondensation,
but within 30 seconds of irradiation, RNF8
protein can be detected in association with
γH2AX.[49] RNF8 mediates extensive
chromatin decondensation, through its
subsequent interaction with CHD4,[50] a
component of the nucleosome remodeling
and deacetylase complex NuRD.
DDB2 occurs in a heterodimeric complex
with DDB1. This complex further
complexes with the ubiquitin ligase protein
CUL4A[51] and with PARP1.[52] This larger
complex rapidly associates with UV-
induced damage within chromatin, with
half-maximum association completed in
40 seconds.[51] The PARP1 protein,
attached to both DDB1 and DDB2, then
PARylates (creates a poly-ADP ribose
chain) on DDB2 that attracts the DNA
remodeling protein ALC1.[52] Action of
ALC1 relaxes the chromatin at the site of
UV damage to DNA. This relaxation allows
other proteins in the nucleotide excision
repair pathway to enter the chromatin and
repair UV-induced cyclobutane pyrimidine
dimer damages.
After rapid chromatin remodeling, cell

cycle checkpoints are activated to allow
DNA repair to occur before the cell cycle
progresses. First, two kinases, ATM and
ATR are activated within 5 or 6 minutes
after DNA is damaged. This is followed by
phosphorylation of the cell cycle
checkpoint protein Chk1, initiating its
function, about 10 minutes after DNA is
damaged.[53]
DNA damage checkpoints

After DNA damage, cell cycle checkpoints
are activated. Checkpoint activation
pauses the cell cycle and gives the cell
time to repair the damage before
continuing to divide. DNA damage
checkpoints occur at the G1/S and G2/M
boundaries. An intra-S checkpoint also
exists. Checkpoint activation is controlled
by two master kinases, ATM and ATR. ATM
responds to DNA double-strand breaks
and disruptions in chromatin structure,[54]
whereas ATR primarily responds to stalled
replication forks. These kinases
phosphorylate downstream targets in a
signal transduction cascade, eventually
leading to cell cycle arrest. A class of
checkpoint mediator proteins including
BRCA1, MDC1, and 53BP1 has also been
identified.[55] These proteins seem to be
required for transmitting the checkpoint
activation signal to downstream proteins.
DNA damage checkpoint is a signal

transduction pathway that blocks cell
cycle progression in G1, G2 and
metaphase and slows down the rate of S
phase progression when DNA is damaged.
It leads to a pause in cell cycle allowing
the cell time to repair the damage before
continuing to divide.
Checkpoint Proteins can be separated into
four groups: phosphatidylinositol 3-kinase
(PI3K)-like protein kinase, proliferating cell
nuclear antigen (PCNA)-like group, two
serine/threonine(S/T) kinases and their
adaptors. Central to all DNA damage
induced checkpoints responses is a pair of
large protein kinases belonging to the first
group of PI3K-like protein kinases-the ATM
(Ataxia telangiectasia mutated) and ATR
(Ataxia- and Rad-related) kinases, whose
sequence and functions have been well
conserved in evolution. All DNA damage
response requires either ATM or ATR
because they have the ability to bind to the
chromosomes at the site of DNA damage,
together with accessory proteins that are
platforms on which DNA damage
response components and DNA repair
complexes can be assembled.
An important downstream target of ATM

and ATR is p53, as it is required for
inducing apoptosis following DNA
damage.[56] The cyclin-dependent kinase
inhibitor p21 is induced by both p53-
dependent and p53-independent
mechanisms and can arrest the cell cycle
at the G1/S and G2/M checkpoints by
deactivating cyclin/cyclin-dependent
kinase complexes.[57]
The prokaryotic SOS response
The SOS response is the changes in gene

expression in Escherichia coli and other
bacteria in response to extensive DNA
damage. The prokaryotic SOS system is
regulated by two key proteins: LexA and
RecA. The LexA homodimer is a
transcriptional repressor that binds to
operator sequences commonly referred to
as SOS boxes. In Escherichia coli it is
known that LexA regulates transcription of
approximately 48 genes including the lexA
and recA genes.[58] The SOS response is
known to be widespread in the Bacteria
domain, but it is mostly absent in some
bacterial phyla, like the Spirochetes.[59] The
most common cellular signals activating
the SOS response are regions of single-
stranded DNA (ssDNA), arising from
stalled replication forks or double-strand
breaks, which are processed by DNA
helicase to separate the two DNA
strands.[42] In the initiation step, RecA
protein binds to ssDNA in an ATP
hydrolysis driven reaction creating RecA–
ssDNA filaments. RecA–ssDNA filaments
activate LexA autoprotease activity, which
ultimately leads to cleavage of LexA dimer
and subsequent LexA degradation. The
loss of LexA repressor induces
transcription of the SOS genes and allows
for further signal induction, inhibition of
cell division and an increase in levels of
proteins responsible for damage
processing.
In Escherichia coli, SOS boxes are 20-

nucleotide long sequences near promoters
with palindromic structure and a high
degree of sequence conservation. In other
classes and phyla, the sequence of SOS
boxes varies considerably, with different
length and composition, but it is always
highly conserved and one of the strongest
short signals in the genome.[59] The high
information content of SOS boxes permits
differential binding of LexA to different
promoters and allows for timing of the
SOS response. The lesion repair genes are
induced at the beginning of SOS response.
The error-prone translesion polymerases,
for example, UmuCD'2 (also called DNA
polymerase V), are induced later on as a
last resort.[60] Once the DNA damage is
repaired or bypassed using polymerases
or through recombination, the amount of
single-stranded DNA in cells is decreased,
lowering the amounts of RecA filaments
decreases cleavage activity of LexA
homodimer, which then binds to the SOS
boxes near promoters and restores normal
gene expression.
Eukaryotic transcriptional responses
to DNA damage
Eukaryotic cells exposed to DNA

damaging agents also activate important
defensive pathways by inducing multiple
proteins involved in DNA repair, cell cycle
checkpoint control, protein trafficking and
degradation. Such genome wide
transcriptional response is very complex
and tightly regulated, thus allowing
coordinated global response to damage.
Exposure of yeast Saccharomyces
cerevisiae to DNA damaging agents
results in overlapping but distinct
transcriptional profiles. Similarities to
environmental shock response indicates
that a general global stress response
pathway exist at the level of transcriptional
activation. In contrast, different human cell
types respond to damage differently
indicating an absence of a common global
response. The probable explanation for
this difference between yeast and human
cells may be in the heterogeneity of
mammalian cells. In an animal different
types of cells are distributed among
different organs that have evolved
different sensitivities to DNA damage.[61]
In general global response to DNA damage

involves expression of multiple genes
responsible for postreplication repair,
homologous recombination, nucleotide
excision repair, DNA damage checkpoint,
global transcriptional activation, genes
controlling mRNA decay, and many others.
A large amount of damage to a cell leaves
it with an important decision: undergo
apoptosis and die, or survive at the cost of
living with a modified genome. An increase
in tolerance to damage can lead to an
increased rate of survival that will allow a
greater accumulation of mutations. Yeast
Rev1 and human polymerase η are
members of Y family translesion DNA
polymerases present during global
response to DNA damage and are
responsible for enhanced mutagenesis
during a global response to DNA damage
in eukaryotes.[42]
Aging
Pathological effects of poor DNA

repair
DNA repair rate is an important determinant of cell pathology.

Experimental animals with genetic
deficiencies in DNA repair often show
decreased life span and increased cancer
incidence.[15] For example, mice deficient
in the dominant NHEJ pathway and in
telomere maintenance mechanisms get
lymphoma and infections more often, and,
as a consequence, have shorter lifespans
than wild-type mice.[62] In similar manner,
mice deficient in a key repair and
transcription protein that unwinds DNA
helices have premature onset of aging-
related diseases and consequent
shortening of lifespan.[63] However, not
every DNA repair deficiency creates
exactly the predicted effects; mice
deficient in the NER pathway exhibited
shortened life span without
correspondingly higher rates of
mutation.[64]
If the rate of DNA damage exceeds the

capacity of the cell to repair it, the
accumulation of errors can overwhelm the
cell and result in early senescence,
apoptosis, or cancer. Inherited diseases
associated with faulty DNA repair
functioning result in premature aging,[15]
increased sensitivity to carcinogens and
correspondingly increased cancer risk (see
below). On the other hand, organisms with
enhanced DNA repair systems, such as
Deinococcus radiodurans, the most
radiation-resistant known organism, exhibit
remarkable resistance to the double-
strand break-inducing effects of
radioactivity, likely due to enhanced
efficiency of DNA repair and especially
NHEJ.[65]
Longevity and caloric restriction

Most life span influencing genes affect the rate of DNA damage.
A number of individual genes have been

identified as influencing variations in life
span within a population of organisms.
The effects of these genes is strongly
dependent on the environment, in
particular, on the organism's diet. Caloric
restriction reproducibly results in extended
lifespan in a variety of organisms, likely via
nutrient sensing pathways and decreased
metabolic rate. The molecular
mechanisms by which such restriction
results in lengthened lifespan are as yet
unclear (see[66] for some discussion);
however, the behavior of many genes
known to be involved in DNA repair is
altered under conditions of caloric
restriction. Several agents reported to
have anti-aging properties have been
shown to attenuate constitutive level of
mTOR signaling, an evidence of reduction
of metabolic activity, and concurrently to
reduce constitutive level of DNA damage
induced by endogenously generated
reactive oxygen species.[67]
For example, increasing the gene dosage

of the gene SIR-2, which regulates DNA
packaging in the nematode worm
Caenorhabditis elegans, can significantly
extend lifespan.[68] The mammalian
homolog of SIR-2 is known to induce
downstream DNA repair factors involved in
NHEJ, an activity that is especially
promoted under conditions of caloric
restriction.[69] Caloric restriction has been
closely linked to the rate of base excision
repair in the nuclear DNA of rodents,[70]
although similar effects have not been
observed in mitochondrial DNA.[71]
The C. elegans gene AGE-1, an upstream

effector of DNA repair pathways, confers
dramatically extended life span under free-
feeding conditions but leads to a decrease
in reproductive fitness under conditions of
caloric restriction.[72] This observation
supports the pleiotropy theory of the
biological origins of aging, which suggests
that genes conferring a large survival
advantage early in life will be selected for
even if they carry a corresponding
disadvantage late in life.
Medicine and DNA repair
modulation
Hereditary DNA repair disorders
Defects in the NER mechanism are

responsible for several genetic disorders,
including:
Xeroderma pigmentosum:
hypersensitivity to sunlight/UV, resulting
in increased skin cancer incidence and
premature aging
Cockayne syndrome: hypersensitivity to
UV and chemical agents
Trichothiodystrophy: sensitive skin,
brittle hair and nails
Mental retardation often accompanies the

latter two disorders, suggesting increased
vulnerability of developmental neurons.
Other DNA repair disorders include:
Werner's syndrome: premature aging

and retarded growth
Bloom's syndrome: sunlight
hypersensitivity, high incidence of
malignancies (especially leukemias).
Ataxia telangiectasia: sensitivity to
ionizing radiation and some chemical
agents
All of the above diseases are often called
"segmental progerias" ("accelerated aging
diseases") because those affected appear
elderly and experience aging-related
diseases at an abnormally young age,
while not manifesting all the symptoms of
old age.
Other diseases associated with reduced

DNA repair function include Fanconi
anemia, hereditary breast cancer and
hereditary colon cancer.
Cancer
Because of inherent limitations in the DNA
repair mechanisms, if humans lived long
enough, they would all eventually develop
cancer.[73][74] There are at least 34
Inherited human DNA repair gene
mutations that increase cancer risk. Many
of these mutations cause DNA repair to be
less effective than normal. In particular,
Hereditary nonpolyposis colorectal cancer
(HNPCC) is strongly associated with
specific mutations in the DNA mismatch
repair pathway. BRCA1 and BRCA2, two
important genes whose mutations confer
a hugely increased risk of breast cancer on
carriers,[75] are both associated with a
large number of DNA repair pathways,
especially NHEJ and homologous
recombination.
Cancer therapy procedures such as
chemotherapy and radiotherapy work by
overwhelming the capacity of the cell to
repair DNA damage, resulting in cell death.
Cells that are most rapidly dividing – most
typically cancer cells – are preferentially
affected. The side-effect is that other non-
cancerous but rapidly dividing cells such
as progenitor cells in the gut, skin, and
hematopoietic system are also affected.
Modern cancer treatments attempt to
localize the DNA damage to cells and
tissues only associated with cancer, either
by physical means (concentrating the
therapeutic agent in the region of the
tumor) or by biochemical means
(exploiting a feature unique to cancer cells
in the body). In the context of therapies
targeting DNA damage response genes,
the latter approach has been termed
'synthetic lethality'.[76]
Perhaps the most well-known of these

'synthetic lethality' drugs is the poly(ADP-
ribose) polymerase 1 (PARP1) inhibitor
olaparib, which was approved by the Food
and Drug Administration in 2015 for the
treatment in women of BRCA-defective
ovarian cancer. Tumor cells with partial
loss of DNA damage response
(specifically, homologous recombination
repair) are dependent on another
mechanism – single-strand break repair –
which is a mechanism consisting, in part,
of the PARP1 gene product.[77] Olaparib is
combined with chemotherapeutics to
inhibit single-strand break repair induced
by DNA damage caused by the co-
administered chemotherapy. Tumor cells
relying on this residual DNA repair
mechanism are unable to repair the
damage and hence are not able to survive
and proliferate, whereas normal cells can
repair the damage with the functioning
homologous recombination mechanism.
Many other drugs for use against other

residual DNA repair mechanisms
commonly found in cancer are currently
under investigation. However, synthetic
lethality therapeutic approaches have been
questioned due to emerging evidence of
acquired resistance, achieved through
rewiring of DNA damage response
pathways and reversion of previously
inhibited defects.[78]
DNA repair defects in cancer
It has become apparent over the past

several years that the DNA damage
response acts as a barrier to the malignant
transformation of preneoplastic cells.[79]
Previous studies have shown an elevated
DNA damage response in cell-culture
models with oncogene activation[80] and
preneoplastic colon adenomas.[81] DNA
damage response mechanisms trigger
cell-cycle arrest, and attempt to repair
DNA lesions or promote cell
death/senescence if repair is not possible.
Replication stress is observed in
preneoplastic cells due to increased
proliferation signals from oncogenic
mutations. Replication stress is
characterized by: increased replication
initiation/origin firing; increased
transcription and collisions of
transcription-replication complexes;
nucleotide deficiency; increase in reactive
oxygen species (ROS).[82]
Replication stress, along with the selection

for inactivating mutations in DNA damage
response genes in the evolution of the
tumor,[83] leads to downregulation and/or
loss of some DNA damage response
mechanisms, and hence loss of DNA
repair and/or senescence/programmed
cell death. In experimental mouse models,
loss of DNA damage response-mediated
cell senescence was observed after using
a short hairpin RNA (shRNA) to inhibit the
double-strand break response kinase
ataxia telangiectasia (ATM), leading to
increased tumor size and invasiveness.[81]
Humans born with inherited defects in DNA
repair mechanisms (for example, Li-
Fraumeni syndrome) have a higher cancer
risk.[84]
The prevalence of DNA damage response

mutations differs across cancer types; for
example, 30% of breast invasive
carcinomas have mutations in genes
involved in homologous recombination.[79]
In cancer, downregulation is observed
across all DNA damage response
mechanisms (base excision repair (BER),
nucleotide excision repair (NER), DNA
mismatch repair (MMR), homologous
recombination repair (HR), non-
homologous end joining (NHEJ) and
translesion DNA synthesis (TLS).[85] As
well as mutations to DNA damage repair
genes, mutations also arise in the genes
responsible for arresting the cell cycle to
allow sufficient time for DNA repair to
occur, and some genes are involved in both
DNA damage repair and cell cycle
checkpoint control, for example ATM and
checkpoint kinase 2 (CHEK2) – a tumor
suppressor that is often absent or
downregulated in non-small cell lung
cancer.[86]
HR NHEJ SSA FA BER NER MMR
ATM
ATR
PAXIP
RPA
BRCA1
BRCA2
RAD51
RFC
XRCC1
PCNA
PARP1
ERCC1
MSH3
Genes involved in DNA damage response pat hways and frequent ly mut at ed in cancer (HR =
homologous recombinat ion; NHEJ = non-homologous end joining; SSA = single-st rand annealing;
FA = fanconi anemia pat hway; BER = base excision repair; NER = nucleot ide excision repair; MMR
= mismat ch repair)
Epigenetic DNA repair defects in

cancer
Classically, cancer has been viewed as a

set of diseases that are driven by
progressive genetic abnormalities that
include mutations in tumour-suppressor
genes and oncogenes, and chromosomal
aberrations. However, it has become
apparent that cancer is also driven by
epigenetic alterations.[87]
Epigenetic alterations refer to functionally

relevant modifications to the genome that
do not involve a change in the nucleotide
sequence. Examples of such
modifications are changes in DNA
methylation (hypermethylation and
hypomethylation) and histone
modification,[88] changes in chromosomal
architecture (caused by inappropriate
expression of proteins such as HMGA2 or
HMGA1)[89] and changes caused by
microRNAs. Each of these epigenetic
alterations serves to regulate gene
expression without altering the underlying
DNA sequence. These changes usually
remain through cell divisions, last for
multiple cell generations, and can be
considered to be epimutations (equivalent
to mutations).
While large numbers of epigenetic

alterations are found in cancers, the
epigenetic alterations in DNA repair genes,
causing reduced expression of DNA repair
proteins, appear to be particularly
important. Such alterations are thought to
occur early in progression to cancer and to
be a likely cause of the genetic instability
characteristic of cancers.[90][91][92]
Reduced expression of DNA repair genes

causes deficient DNA repair. When DNA
repair is deficient DNA damages remain in
cells at a higher than usual level and these
excess damages cause increased
frequencies of mutation or epimutation.
Mutation rates increase substantially in
cells defective in DNA mismatch
repair[93][94] or in homologous
recombinational repair (HRR).[95]
Chromosomal rearrangements and
aneuploidy also increase in HRR defective
cells.[96]
Higher levels of DNA damage not only

cause increased mutation, but also cause
increased epimutation. During repair of
DNA double strand breaks, or repair of
other DNA damages, incompletely cleared
sites of repair can cause epigenetic gene
silencing.[97][98]
Deficient expression of DNA repair

proteins due to an inherited mutation can
cause increased risk of cancer. Individuals
with an inherited impairment in any of 34
DNA repair genes (see article DNA repair-
deficiency disorder) have an increased risk
of cancer, with some defects causing up to
a 100% lifetime chance of cancer (e.g. p53
mutations).[99] However, such germline
mutations (which cause highly penetrant
cancer syndromes) are the cause of only
about 1 percent of cancers.[100]
Frequencies of epimutations in DNA

repair genes
A chart of common DNA damaging agents, examples of lesions they cause in DNA, and pathways used to repair these
lesions. Also shown are many of the genes in these pathways, an indication of which genes are epigenetically
regulated to have reduced (or increased) expression in various cancers. It also shows genes in the error-prone
microhomology-mediated end joining pathway with increased expression in various cancers.
Deficiencies in DNA repair enzymes are

occasionally caused by a newly arising
somatic mutation in a DNA repair gene, but
are much more frequently caused by
epigenetic alterations that reduce or
silence expression of DNA repair genes.
For example, when 113 colorectal cancers
were examined in sequence, only four had
a missense mutation in the DNA repair
gene MGMT, while the majority had
reduced MGMT expression due to
methylation of the MGMT promoter region
(an epigenetic alteration).[101] Five different
studies found that between 40% and 90%
of colorectal cancers have reduced MGMT
expression due to methylation of the
MGMT promoter region.[102][103][104][105][106]
Similarly, out of 119 cases of mismatch

repair-deficient colorectal cancers that
lacked DNA repair gene PMS2 expression,
PMS2 was deficient in 6 due to mutations
in the PMS2 gene, while in 103 cases
PMS2 expression was deficient because
its pairing partner MLH1 was repressed
due to promoter methylation (PMS2
protein is unstable in the absence of
MLH1).[107] In the other 10 cases, loss of
PMS2 expression was likely due to
epigenetic overexpression of the
microRNA, miR-155, which down-regulates
MLH1.[108]
In a further example, epigenetic defects

were found in various cancers (e.g. breast,
ovarian, colorectal and head and neck).
Two or three deficiencies in the expression
of ERCC1, XPF or PMS2 occur
simultaneously in the majority of 49 colon
cancers evaluated by Facista et al.[109]
The chart in this section shows some

frequent DNA damaging agents, examples
of DNA lesions they cause, and the
pathways that deal with these DNA
damages. At least 169 enzymes are either
directly employed in DNA repair or
influence DNA repair processes.[110] Of
these, 83 are directly employed in repairing
the 5 types of DNA damages illustrated in
the chart.
Some of the more well studied genes
central to these repair processes are
shown in the chart. The gene designations
shown in red, gray or cyan indicate genes
frequently epigenetically altered in various
types of cancers. Wikipedia articles on
each of the genes highlighted by red, gray
or cyan describe the epigenetic
alteration(s) and the cancer(s) in which
these epimutations are found. Review
articles,[111] and broad experimental
survey articles[112][113] also document
most of these epigenetic DNA repair
deficiencies in cancers.
Red-highlighted genes are frequently
reduced or silenced by epigenetic
mechanisms in various cancers. When
these genes have low or absent
expression, DNA damages can
accumulate. Replication errors past these
damages (see translesion synthesis) can
lead to increased mutations and,
ultimately, cancer. Epigenetic repression of
DNA repair genes in accurate DNA repair
pathways appear to be central to
carcinogenesis.
The two gray-highlighted genes RAD51 and

BRCA2, are required for homologous
recombinational repair. They are
sometimes epigenetically over-expressed
and sometimes under-expressed in certain
cancers. As indicated in the Wikipedia
articles on RAD51 and BRCA2, such
cancers ordinarily have epigenetic
deficiencies in other DNA repair genes.
These repair deficiencies would likely
cause increased unrepaired DNA
damages. The over-expression of RAD51
and BRCA2 seen in these cancers may
reflect selective pressures for
compensatory RAD51 or BRCA2 over-
expression and increased homologous
recombinational repair to at least partially
deal with such excess DNA damages. In
those cases where RAD51 or BRCA2 are
under-expressed, this would itself lead to
increased unrepaired DNA damages.
Replication errors past these damages
(see translesion synthesis) could cause
increased mutations and cancer, so that
under-expression of RAD51 or BRCA2
would be carcinogenic in itself.
Cyan-highlighted genes are in the

microhomology-mediated end joining
(MMEJ) pathway and are up-regulated in
cancer. MMEJ is an additional error-prone
inaccurate repair pathway for double-
strand breaks. In MMEJ repair of a double-
strand break, an homology of 5–25
complementary base pairs between both
paired strands is sufficient to align the
strands, but mismatched ends (flaps) are
usually present. MMEJ removes the extra
nucleotides (flaps) where strands are
joined, and then ligates the strands to
create an intact DNA double helix. MMEJ
almost always involves at least a small
deletion, so that it is a mutagenic
pathway.[24] FEN1, the flap endonuclease
in MMEJ, is epigenetically increased by
promoter hypomethylation and is over-
expressed in the majority of cancers of the
breast,[114] prostate,[115] stomach,[116][117]
neuroblastomas,[118] pancreas,[119] and
lung.[120] PARP1 is also over-expressed
when its promoter region ETS site is
epigenetically hypomethylated, and this
contributes to progression to endometrial
cancer[121] and BRCA-mutated serous
ovarian cancer.[122] Other genes in the
MMEJ pathway are also over-expressed in
a number of cancers (see MMEJ for
summary), and are also shown in cyan.
Genome-wide distribution of DNA

repair in human somatic cells
Differential activity of DNA repair pathways

across various regions of the human
genome causes mutations to be very
unevenly distributed within tumor
genomes.[123][124] In particular, the gene-
rich, early-replicating regions of the human
genome exhibit lower mutation
frequencies than the gene-poor, late-
replicating heterochromatin. One
mechanism underlying this involves the
histone modification H3K36me3, which
can recruit mismatch repair proteins,[125]
thereby lowering mutation rates in
H3K36me3-marked regions.[126] Another
important mechanism concerns nucleotide
excision repair, which can be recruited by
the transcription machinery, lowering
somatic mutation rates in active genes[124]
and other open chromatin regions.[127]
Epigenetic alterations due to

DNA repair
Damage to DNA is very common and is
constantly being repaired. Epigenetic
alterations can accompany DNA repair of
oxidative damage or double-strand breaks.
In human cells, oxidative DNA damage
occurs about 10,000 times a day and DNA
double-strand breaks occur about 10 to 50
times a cell cycle in somatic replicating
cells (see DNA damage (naturally
occurring)). The selective advantage of
DNA repair is to allow the cell to survive in
the face of DNA damage. The selective
advantage of epigenetic alterations that
occur with DNA repair is not clear.
Repair of oxidative DNA damage can
alter epigenetic markers
In the steady state (with endogenous

damages occurring and being repaired),
there are about 2,400 oxidatively damaged
guanines that form 8-oxo-2'-
deoxyguanosine (8-OHdG) in the average
mammalian cell DNA.[128] 8-OHdG
constitutes about 5% of the oxidative
damages commonly present in DNA.[129]
The oxidized guanines do not occur
randomly among all guanines in DNA.
There is a sequence preference for the
guanine at a methylated CpG site (a
cytosine followed by guanine along its 5'
→ 3' direction and where the cytosine is
methylated (5-mCpG)).[130] A 5-mCpG site
has the lowest ionization potential for
guanine oxidation.
Initiation of DNA demethylation at a CpG site. In adult somatic cells DNA methylation typically occurs in the context of
CpG dinucleotides (CpG sites), forming 5-methylcytosine-pG, or 5mCpG. Reactive oxygen species (ROS) may attack
guanine at the dinucleotide site, forming 8-hydroxy-2'-deoxyguanosine (8-OHdG), and resulting in a 5mCp-8-OHdG
dinucleotide site. The base excision repair enzyme OGG1 targets 8-OHdG and binds to the lesion without immediate
excision. OGG1, present at a 5mCp-8-OHdG site recruits TET1 and TET1 oxidizes the 5mC adjacent to the 8-OHdG. This
initiates demethylation of 5mC.[131]
Oxidized guanine has mispairing potential

and is mutagenic.[132] Oxoguanine
glycosylase (OGG1) is the primary enzyme
responsible for the excision of the oxidized
guanine during DNA repair. OGG1 finds and
binds to an 8-OHdG within a few
seconds.[133] However, OGG1 does not
immediately excise 8-OHdG. In HeLa cells
half maximum removal of 8-OHdG occurs
in 30 minutes,[134] and in irradiated mice,
the 8-OHdGs induced in the mouse liver
are removed with a half-life of 11
minutes.[129]
When OGG1 is present at an oxidized

guanine within a methylated CpG site it
recruits TET1 to the 8-OHdG lesion (see
Figure). This allows TET1 to demethylate
an adjacent methylated cytosine.
Demethylation of cytosine is an epigenetic
alteration.
As an example, when human mammary

epithelial cells were treated with H2O2 for
six hours, 8-OHdG increased about 3.5-
fold in DNA and this caused about 80%
demethylation of the 5-methylcytosines in
the genome.[131] Demethylation of CpGs in
a gene promoter by TET enzyme activity
increases transcription of the gene into
messenger RNA.[135] In cells treated with
H2O2, one particular gene was examined,
BACE1.[131] The methylation level of the
BACE1 CpG island was reduced (an
epigenetic alteration) and this allowed
about 6.5 fold increase of expression of
BACE1 messenger RNA.
While six-hour incubation with H2O2 causes

considerable demethylation of 5-mCpG
sites, shorter times of H2O2 incubation
appear to promote other epigenetic
alterations. Treatment of cells with H2O2
for 30 minutes causes the mismatch repair
protein heterodimer MSH2-MSH6 to recruit
DNA methyltransferase 1 (DNMT1) to sites
of some kinds of oxidative DNA
damage.[136] This could cause increased
methylation of cytosines (epigenetic
alterations) at these locations.
Jiang et al.[137] treated HEK 293 cells with
agents causing oxidative DNA damage,
(potassium bromate (KBrO3) or potassium
chromate (K2CrO4)). Base excision repair
(BER) of oxidative damage occurred with
the DNA repair enzyme polymerase beta
localizing to oxidized guanines.
Polymerase beta is the main human
polymerase in short-patch BER of
oxidative DNA damage. Jiang et al.[137]
also found that polymerase beta recruited
the DNA methyltransferase protein
DNMT3b to BER repair sites. They then
evaluated the methylation pattern at the
single nucleotide level in a small region of
DNA including the promoter region and the
early transcription region of the BRCA1
gene. Oxidative DNA damage from
bromate modulated the DNA methylation
pattern (caused epigenetic alterations) at
CpG sites within the region of DNA
studied. In untreated cells, CpGs located
at −189, −134, −29, −19, +16, and +19 of
the BRCA1 gene had methylated cytosines
(where numbering is from the messenger
RNA transcription start site, and negative
numbers indicate nucleotides in the
upstream promoter region). Bromate
treatment-induced oxidation resulted in the
loss of cytosine methylation at −189,
−134, +16 and +19 while also leading to
the formation of new methylation at the
CpGs located at −80, −55, −21 and +8
after DNA repair was allowed.
Homologous recombinational repair

alters epigenetic markers
At least four articles report the recruitment

of DNA methyltransferase 1 (DNMT1) to
sites of DNA double-strand
breaks.[138][139][140][141] During homologous
recombinational repair (HR) of the double-
strand break, the involvement of DNMT1
causes the two repaired strands of DNA to
have different levels of methylated
cytosines. One strand becomes frequently
methylated at about 21 CpG sites
downstream of the repaired double-strand
break. The other DNA strand loses
methylation at about six CpG sites that
were previously methylated downstream
of the double-strand break, as well as
losing methylation at about five CpG sites
that were previously methylated upstream
of the double-strand break. When the
chromosome is replicated, this gives rise
to one daughter chromosome that is
heavily methylated downstream of the
previous break site and one that is
unmethylated in the region both upstream
and downstream of the previous break
site. With respect to the gene that was
broken by the double-strand break, half of
the progeny cells express that gene at a
high level and in the other half of the
progeny cells expression of that gene is
repressed. When clones of these cells
were maintained for three years, the new
methylation patterns were maintained over
that time period.[142]
In mice with a CRISPR-mediated

homology-directed recombination
insertion in their genome there were a large
number of increased methylations of CpG
sites within the double-strand break-
associated insertion.[143]
Non-homologous end joining can

cause some epigenetic marker
alterations
Non-homologous end joining (NHEJ) repair

of a double-strand break can cause a
small number of demethylations of pre-
existing cytosine DNA methylations
downstream of the repaired double-strand
break.[139] Further work by Allen et al.[144]
showed that NHEJ of a DNA double-strand
break in a cell could give rise to some
progeny cells having repressed expression
of the gene harboring the initial double-
strand break and some progeny having
high expression of that gene due to
epigenetic alterations associated with
NHEJ repair. The frequency of epigenetic
alterations causing repression of a gene
after an NHEJ repair of a DNA double-
strand break in that gene may be about
0.9%.[140]
Evolution
The basic processes of DNA repair are
highly conserved among both prokaryotes
and eukaryotes and even among
bacteriophages (viruses which infect
bacteria); however, more complex
organisms with more complex genomes
have correspondingly more complex repair
mechanisms.[145] The ability of a large
number of protein structural motifs to
catalyze relevant chemical reactions has
played a significant role in the elaboration
of repair mechanisms during evolution. For
an extremely detailed review of
hypotheses relating to the evolution of
DNA repair, see.[146]
The fossil record indicates that single-cell

life began to proliferate on the planet at
some point during the Precambrian period,
although exactly when recognizably
modern life first emerged is unclear.
Nucleic acids became the sole and
universal means of encoding genetic
information, requiring DNA repair
mechanisms that in their basic form have
been inherited by all extant life forms from
their common ancestor. The emergence of
Earth's oxygen-rich atmosphere (known as
the "oxygen catastrophe") due to
photosynthetic organisms, as well as the
presence of potentially damaging free
radicals in the cell due to oxidative
phosphorylation, necessitated the
evolution of DNA repair mechanisms that
act specifically to counter the types of
damage induced by oxidative stress.
Rate of evolutionary change

On some occasions, DNA damage is not
repaired or is repaired by an error-prone
mechanism that results in a change from
the original sequence. When this occurs,
mutations may propagate into the
genomes of the cell's progeny. Should
such an event occur in a germ line cell that
will eventually produce a gamete, the
mutation has the potential to be passed on
to the organism's offspring. The rate of
evolution in a particular species (or, in a
particular gene) is a function of the rate of
mutation. As a consequence, the rate and
accuracy of DNA repair mechanisms have
an influence over the process of
evolutionary change.[147] DNA damage
protection and repair does not influence
the rate of adaptation by gene regulation
and by recombination and selection of
alleles. On the other hand, DNA damage
repair and protection does influence the
rate of accumulation of irreparable,
advantageous, code expanding, inheritable
mutations, and slows down the
evolutionary mechanism for expansion of
the genome of organisms with new
functionalities. The tension between
evolvability and mutation repair and
protection needs further investigation.
Technology
A technology named clustered regularly
interspaced short palindromic repeat
(shortened to CRISPR-Cas9) was
discovered in 2012. The new technology
allows anyone with molecular biology
training to alter the genes of any species
with precision, by inducing DNA damage at
a specific point and then altering DNA
repair mechanisms to insert new
genes.[148] It is cheaper, more efficient, and
more precise than other technologies. With
the help of CRISPR–Cas9, parts of a
genome can be edited by scientists by
removing, adding, or altering parts in a
DNA sequence.
See also
Biology
portal
Accelerated aging disease

Aging DNA
Cell cycle
DNA damage (naturally occurring)
DNA damage theory of aging
DNA replication
Direct DNA damage
Gene therapy
Human mitochondrial genetics
Indirect DNA damage
Life extension
Progeria
REPAIRtoire
Senescence
SiDNA
The scientific journal DNA Repair under
Mutation Research
References
1. "Nature Reviews Series: DNA damage" (htt
ps://www.nature.com/collections/hwnqq
cstyj) . Nature Reviews Molecular Cell
Biology. 5 July 2017. Retrieved
7 November 2018.
2. Lodish H, Berk A, Matsudaira P, Kaiser CA,
Krieger M, Scott MP, Zipursky SL, Darnell J
(2004). Molecular Biology of the Cell
(5th ed.). New York: WH Freeman. p. 963.
3. Acharya PV (1971). "The isolation and
partial characterization of age-correlated
oligo-deoxyribo-ribonucleotides with
covalently linked aspartyl-glutamyl
polypeptides". Johns Hopkins Medical
Journal. Supplement (1): 254–60.
PMID 5055816 (https://pubmed.ncbi.nlm.
nih.gov/5055816) .
4. Bjorksten J, Acharya PV, Ashman S,
Wetlaufer DB (July 1971). "Gerogenic
fractions in the tritiated rat". Journal of the
American Geriatrics Society. 19 (7): 561–
74. doi:10.1111/j.1532-
5415.1971.tb02577.x (https://doi.org/10.1
111%2Fj.1532-5415.1971.tb02577.x) .
nih.gov/5106728) . S2CID 33154242 (http
s://api.semanticscholar.org/CorpusID:331
54242) .
5. Browner WS, Kahn AJ, Ziv E, Reiner AP,
Oshima J, Cawthon RM, et al. (December
2004). "The genetics of human longevity".
The American Journal of Medicine. 117
(11): 851–60. CiteSeerX 10.1.1.556.6874
(https://citeseerx.ist.psu.edu/viewdoc/su
mmary?doi=10.1.1.556.6874) .
doi:10.1016/j.amjmed.2004.06.033 (http
s://doi.org/10.1016%2Fj.amjmed.2004.0
6.033) . PMID 15589490 (https://pubmed.
ncbi.nlm.nih.gov/15589490) .
6. Broad WJ (7 October 2015). "Nobel Prize
in Chemistry Awarded to Tomas Lindahl,
Paul Modrich and Aziz Sancar for DNA
Studies" (https://www.nytimes.com/2015/
10/08/science/tomas-lindahl-paul-modric
h-aziz-sancarn-nobel-chemistry.html) .
The New York Times. Retrieved 7 October
2015.
7. Staff (7 October 2015). "The Nobel Prize in
Chemistry 2015 – DNA repair – providing
chemical stability for life" (https://www.no
belprize.org/nobel_prizes/chemistry/laure
ates/2015/popular-chemistryprize2015.p
df) (PDF). Nobel Prize. Retrieved
7 October 2015.
8. Roulston A, Marcellus RC, Branton PE
(1999). "Viruses and apoptosis". Annual
Review of Microbiology. 53: 577–628.
doi:10.1146/annurev.micro.53.1.577 (http
s://doi.org/10.1146%2Fannurev.micro.53.
9. Madigan MT, Martino JM (2006). Brock
Biology of Microorganisms (11th ed.).
Pearson. p. 136. ISBN 978-0-13-196893-6.
10. Ohta T, Tokishita SI, Mochizuki K, Kawase
J, Sakahira M, Yamagata H (2006). "UV
Sensitivity and Mutagenesis of the
Extremely Thermophilic Eubacterium
Thermus thermophilus HB27" (https://doi.
org/10.3123%2Fjemsge.28.56) . Genes
and Environment. 28 (2): 56–61.
doi:10.3123/jemsge.28.56 (https://doi.or
g/10.3123%2Fjemsge.28.56) .
11. Tanaka T, Halicka HD, Huang X, Traganos
F, Darzynkiewicz Z (September 2006).
"Constitutive histone H2AX
phosphorylation and ATM activation, the
reporters of DNA damage by endogenous
oxidants" (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC3488278) . Cell Cycle. 5
(17): 1940–45. doi:10.4161/cc.5.17.3191
(https://doi.org/10.4161%2Fcc.5.17.319
1) . PMC 3488278 (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3488278) .
PMID 16940754 (https://pubmed.ncbi.nl
m.nih.gov/16940754) .
12. Braig M, Schmitt CA (March 2006).
"Oncogene-induced senescence: putting
the brakes on tumor development" (http
s://doi.org/10.1158%2F0008-5472.CAN-0
5-4006) . Cancer Research. 66 (6): 2881–
84. doi:10.1158/0008-5472.CAN-05-4006
(https://doi.org/10.1158%2F0008-5472.C
AN-05-4006) . PMID 16540631 (https://pu
bmed.ncbi.nlm.nih.gov/16540631) .
13. Lynch MD (February 2006). "How does
cellular senescence prevent cancer?".
DNA and Cell Biology. 25 (2): 69–78.
doi:10.1089/dna.2006.25.69 (https://doi.o
rg/10.1089%2Fdna.2006.25.69) .
m.nih.gov/16460230) .
14. Campisi J, d'Adda di Fagagna F
(September 2007). "Cellular senescence:
when bad things happen to good cells".
Nature Reviews. Molecular Cell Biology. 8
(9): 729–40. doi:10.1038/nrm2233 (http
s://doi.org/10.1038%2Fnrm2233) .
m.nih.gov/17667954) . S2CID 15664931
(https://api.semanticscholar.org/CorpusI
D:15664931) .
15. Best BP (June 2009). "Nuclear DNA
damage as a direct cause of aging" (http
s://web.archive.org/web/2017111519250
9/http://www.benbest.com/lifeext/Nuclea
r_DNA_in_Aging.pdf) (PDF). Rejuvenation
Research. 12 (3): 199–208.
CiteSeerX 10.1.1.318.738 (https://citeseer
x.ist.psu.edu/viewdoc/summary?doi=10.
1.1.318.738) . doi:10.1089/rej.2009.0847
(https://doi.org/10.1089%2Frej.2009.084
7) . PMID 19594328 (https://pubmed.ncb
i.nlm.nih.gov/19594328) . Archived from
the original (http://www.benbest.com/lifee
xt/Nuclear_DNA_in_Aging.pdf) (PDF) on
15 November 2017. Retrieved
29 September 2009.
16. Sancar A (June 2003). "Structure and
function of DNA photolyase and
cryptochrome blue-light photoreceptors".
Chemical Reviews. 103 (6): 2203–37.
doi:10.1021/cr0204348 (https://doi.org/1
0.1021%2Fcr0204348) . PMID 12797829
(https://pubmed.ncbi.nlm.nih.gov/12797
829) .
17. Lucas-Lledó JI, Lynch M (May 2009).
"Evolution of mutation rates:
phylogenomic analysis of the
photolyase/cryptochrome family" (https://
www.ncbi.nlm.nih.gov/pmc/articles/PMC
2668831) . Molecular Biology and
Evolution. 26 (5): 1143–53.
doi:10.1093/molbev/msp029 (https://doi.
org/10.1093%2Fmolbev%2Fmsp029) .
PMC 2668831 (https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC2668831) .
m.nih.gov/19228922) .
18. Watson JD, Baker TA, Bell SP, Gann A,
Levine M, Losick R (2004). Molecular
Biology of the Gene (5th ed.). Pearson
Benjamin Cummings; CSHL Press. Ch. 9,
10. OCLC 936762772 (https://www.worldc
at.org/oclc/936762772) .
19. Volkert MR (1988). "Adaptive response of
Escherichia coli to alkylation damage".
Environmental and Molecular
Mutagenesis. 11 (2): 241–55.
doi:10.1002/em.2850110210 (https://doi.
org/10.1002%2Fem.2850110210) .
nih.gov/3278898) . S2CID 24722637 (http
s://api.semanticscholar.org/CorpusID:247
22637) .
20. Willey J, Sherwood L, Woolverton C
(2014). Prescott's Microbiology. New York:
McGraw Hill. p. 381. ISBN 978-0-07-3402-
40-6.
21. Russell P (2018). i Genetics. Chennai:
Pearson. p. 186. ISBN 978-93-325-7162-4.
22. Reardon JT, Sancar A (2006). "Purification
and characterization of Escherichia coli
and human nucleotide excision repair
enzyme systems". Methods in
Enzymology. 408: 189–213.
doi:10.1016/S0076-6879(06)08012-8 (http
s://doi.org/10.1016%2FS0076-6879%280
6%2908012-8) . ISBN 9780121828134.
m.nih.gov/16793370) .
23. Berg M, Tymoczko J, Stryer L (2012).
Biochemistry 7th edition. New York: W.H.
Freeman and Company. p. 840.
ISBN 9781429229364.
24. Liang L, Deng L, Chen Y, Li GC, Shao C,
Tischfield JA (September 2005).
"Modulation of DNA end joining by nuclear
proteins" (https://doi.org/10.1074%2Fjbc.
M503776200) . The Journal of Biological
Chemistry. 280 (36): 31442–49.
doi:10.1074/jbc.M503776200 (https://doi.
org/10.1074%2Fjbc.M503776200) .
m.nih.gov/16012167) .
25. Wilson TE, Grawunder U, Lieber MR (July
1997). "Yeast DNA ligase IV mediates non-
homologous DNA end joining" (https://doi.
org/10.1038%2F41365) . Nature. 388
(6641): 495–98.
Bibcode:1997Natur.388..495W (https://ui.
adsabs.harvard.edu/abs/1997Natur.388..
495W) . doi:10.1038/41365 (https://doi.or
g/10.1038%2F41365) . PMID 9242411 (ht
tps://pubmed.ncbi.nlm.nih.gov/9242411)
. S2CID 4422938 (https://api.semanticsch
olar.org/CorpusID:4422938) .
26. Moore JK, Haber JE (May 1996). "Cell
cycle and genetic requirements of two
pathways of nonhomologous end-joining
repair of double-strand breaks in
Saccharomyces cerevisiae" (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC2312
04) . Molecular and Cellular Biology. 16
(5): 2164–73. doi:10.1128/mcb.16.5.2164
(https://doi.org/10.1128%2Fmcb.16.5.21
nih.gov/8628283) .
27. Boulton SJ, Jackson SP (September
1996). "Saccharomyces cerevisiae Ku70
potentiates illegitimate DNA double-strand
break repair and serves as a barrier to
error-prone DNA repair pathways" (https://
452249) . The EMBO Journal. 15 (18):
5093–103. doi:10.1002/j.1460-
2075.1996.tb00890.x (https://doi.org/10.1
002%2Fj.1460-2075.1996.tb00890.x) .
PMC 452249 (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC452249) .
nih.gov/8890183) .
28. Wilson TE, Lieber MR (August 1999).
"Efficient processing of DNA ends during
yeast nonhomologous end joining.
Evidence for a DNA polymerase beta
(Pol4)-dependent pathway" (https://doi.or
g/10.1074%2Fjbc.274.33.23599) . The
Journal of Biological Chemistry. 274 (33):
23599–609.
doi:10.1074/jbc.274.33.23599 (https://do
i.org/10.1074%2Fjbc.274.33.23599) .
m.nih.gov/10438542) .
29. Budman J, Chu G (February 2005).
"Processing of DNA for nonhomologous
end-joining by cell-free extract" (https://w
ww.ncbi.nlm.nih.gov/pmc/articles/PMC54
9622) . The EMBO Journal. 24 (4): 849–
60. doi:10.1038/sj.emboj.7600563 (http
s://doi.org/10.1038%2Fsj.emboj.760056
3) . PMC 549622 (https://www.ncbi.nlm.ni
h.gov/pmc/articles/PMC549622) .
m.nih.gov/15692565) .
30. Wang H, Perrault AR, Takeda Y, Qin W,
Wang H, Iliakis G (September 2003).
"Biochemical evidence for Ku-independent
backup pathways of NHEJ" (https://www.
ncbi.nlm.nih.gov/pmc/articles/PMC2033
13) . Nucleic Acids Research. 31 (18):
5377–88. doi:10.1093/nar/gkg728 (http
s://doi.org/10.1093%2Fnar%2Fgkg728) .
PMC 203313 (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC203313) .
m.nih.gov/12954774) .
31. Jung D, Alt FW (January 2004).
"Unraveling V(D)J recombination; insights
into gene regulation" (https://doi.org/10.1
016%2FS0092-8674%2804%2900039-X) .
Cell. 116 (2): 299–311.
doi:10.1016/S0092-8674(04)00039-X (htt
ps://doi.org/10.1016%2FS0092-8674%280
4%2900039-X) . PMID 14744439 (https://
pubmed.ncbi.nlm.nih.gov/14744439) .
S2CID 16890458 (https://api.semanticsch
32. Truong LN, Li Y, Shi LZ, Hwang PY, He J,
Wang H, et al. (May 2013).
"Microhomology-mediated End Joining
and Homologous Recombination share
the initial end resection step to repair DNA
double-strand breaks in mammalian cells"
(https://www.ncbi.nlm.nih.gov/pmc/articl
es/PMC3651503) . Proceedings of the
National Academy of Sciences of the
United States of America. 110 (19): 7720–
25. Bibcode:2013PNAS..110.7720T (http
s://ui.adsabs.harvard.edu/abs/2013PNA
S..110.7720T) .
doi:10.1073/pnas.1213431110 (https://do
i.org/10.1073%2Fpnas.1213431110) .
m.nih.gov/23610439) .
33. Sharma S, Javadekar SM, Pandey M,
Srivastava M, Kumari R, Raghavan SC
(March 2015). "Homology and enzymatic
requirements of microhomology-
dependent alternative end joining" (http
s://www.ncbi.nlm.nih.gov/pmc/articles/P
MC4385936) . Cell Death & Disease. 6 (3):
e1697. doi:10.1038/cddis.2015.58 (http
s://doi.org/10.1038%2Fcddis.2015.58) .
m.nih.gov/25789972) .
34. Decottignies A (2013). "Alternative end-
joining mechanisms: a historical
perspective" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC3613618) . Frontiers
in Genetics. 4: 48.
doi:10.3389/fgene.2013.00048 (https://do
i.org/10.3389%2Ffgene.2013.00048) .
m.nih.gov/23565119) .
35. Zahradka K, Slade D, Bailone A, Sommer S,
Averbeck D, Petranovic M, et al. (October
2006). "Reassembly of shattered
chromosomes in Deinococcus
radiodurans". Nature. 443 (7111): 569–73.
Bibcode:2006Natur.443..569Z (https://ui.a
dsabs.harvard.edu/abs/2006Natur.443..5
69Z) . doi:10.1038/nature05160 (https://d
oi.org/10.1038%2Fnature05160) .
m.nih.gov/17006450) . S2CID 4412830 (h
ttps://api.semanticscholar.org/CorpusID:4
412830) .
36. Stenerlöw B, Karlsson KH, Cooper B,
Rydberg B. "Measurement of prompt DNA
double-strand breaks in mammalian cells
without including heat-labile sites: results
for cells deficient in nonhomologous end
joining". Radiat Res. 2003 Apr;159(4):502–
10. doi:10.1667/0033-
7587(2003)159[0502:mopdds (https://doi.
org/10.1667%2F0033-7587%282003%291
59%5B0502%3Amopdds%5D2.0.co%3B2)
2.0.co;2] PMID 12643795 (https://pubme
d.ncbi.nlm.nih.gov/12643795) .
37. Waters LS, Minesinger BK, Wiltrout ME,
D'Souza S, Woodruff RV, Walker GC
(March 2009). "Eukaryotic translesion
polymerases and their roles and
regulation in DNA damage tolerance" (http
MC2650891) . Microbiology and
Molecular Biology Reviews. 73 (1): 134–
54. doi:10.1128/MMBR.00034-08 (https://
doi.org/10.1128%2FMMBR.00034-08) .
m.nih.gov/19258535) .
38. Colis LC, Raychaudhury P, Basu AK
(August 2008). "Mutational specificity of
gamma-radiation-induced guanine-
thymine and thymine-guanine intrastrand
cross-links in mammalian cells and
translesion synthesis past the guanine-
thymine lesion by human DNA polymerase
eta" (https://www.ncbi.nlm.nih.gov/pmc/a
rticles/PMC2646719) . Biochemistry. 47
(31): 8070–79. doi:10.1021/bi800529f (htt
ps://doi.org/10.1021%2Fbi800529f) .
m.nih.gov/18616294) .
39. Raychaudhury P, Basu AK (March 2011).
"Genetic requirement for mutagenesis of
the G[8,5-Me]T cross-link in Escherichia
coli: DNA polymerases IV and V compete
for error-prone bypass" (https://www.ncbi.
nlm.nih.gov/pmc/articles/PMC3062377) .
Biochemistry. 50 (12): 2330–38.
doi:10.1021/bi102064z (https://doi.org/1
0.1021%2Fbi102064z) . PMC 3062377 (ht
tps://www.ncbi.nlm.nih.gov/pmc/articles/
PMC3062377) . PMID 21302943 (https://
40. "Translesion Synthesis" (https://web.archi
ve.org/web/20120310104318/http://resea
rch.chem.psu.edu/sjbgroup/projects/tran
slesion.htm) . Research.chem.psu.edu.
Archived from the original (http://researc
h.chem.psu.edu/sjbgroup/projects/transle
sion.htm) on 10 March 2012. Retrieved
14 August 2012.
41. Wang Z (July 2001). "Translesion
synthesis by the UmuC family of DNA
polymerases". Mutation Research. 486 (2):
59–70. doi:10.1016/S0921-
8777(01)00089-1 (https://doi.org/10.101
6%2FS0921-8777%2801%2900089-1) .
m.nih.gov/11425512) .
42. Friedberg EC, Walker GC, Siede W, Wood
RD, Schultz RA, Ellenberger T. (2006). DNA
Repair and Mutagenesis, part 3. ASM
Press. 2nd ed.
43. Liu B, Yip RK, Zhou Z (November 2012).
"Chromatin remodeling, DNA damage
repair and aging" (https://www.ncbi.nlm.ni
Current Genomics. 13 (7): 533–47.
doi:10.2174/138920212803251373 (http
s://doi.org/10.2174%2F13892021280325
1373) . PMC 3468886 (https://www.ncbi.n
lm.nih.gov/pmc/articles/PMC3468886) .
m.nih.gov/23633913) .
44. Halicka HD, Zhao H, Podhorecka M,
Traganos F, Darzynkiewicz Z (July 2009).
"Cytometric detection of chromatin
relaxation, an early reporter of DNA
damage response" (https://www.ncbi.nlm.
nih.gov/pmc/articles/PMC3856216) . Cell
Cycle. 8 (14): 2233–37.
doi:10.4161/cc.8.14.8984 (https://doi.org/
10.4161%2Fcc.8.14.8984) . PMC 3856216
es/PMC3856216) . PMID 19502789 (http
s://pubmed.ncbi.nlm.nih.gov/19502789) .
45. Sellou H, Lebeaupin T, Chapuis C, Smith R,
Hegele A, Singh HR, et al. (December
2016). "The poly(ADP-ribose)-dependent
chromatin remodeler Alc1 induces local
chromatin relaxation upon DNA damage"
es/PMC5170603) . Molecular Biology of
the Cell. 27 (24): 3791–99.
doi:10.1091/mbc.E16-05-0269 (https://do
i.org/10.1091%2Fmbc.E16-05-0269) .
m.nih.gov/27733626) .
46. Van Meter M, Simon M, Tombline G, May
A, Morello TD, Hubbard BP, et al.
(September 2016). "JNK Phosphorylates
SIRT6 to Stimulate DNA Double-Strand
Break Repair in Response to Oxidative
Stress by Recruiting PARP1 to DNA
Breaks" (https://www.ncbi.nlm.nih.gov/pm
c/articles/PMC5089070) . Cell Reports.
16 (10): 2641–50.
doi:10.1016/j.celrep.2016.08.006 (https://
doi.org/10.1016%2Fj.celrep.2016.08.006)
. PMC 5089070 (https://www.ncbi.nlm.nih.
m.nih.gov/27568560) .
47. Haince JF, McDonald D, Rodrigue A, Déry
U, Masson JY, Hendzel MJ, Poirier GG
(January 2008). "PARP1-dependent
kinetics of recruitment of MRE11 and
NBS1 proteins to multiple DNA damage
sites" (https://doi.org/10.1074%2Fjbc.M7
06734200) . The Journal of Biological
Chemistry. 283 (2): 1197–208.
doi:10.1074/jbc.M706734200 (https://doi.
org/10.1074%2Fjbc.M706734200) .
m.nih.gov/18025084) .
48. Rogakou EP, Pilch DR, Orr AH, Ivanova VS,
Bonner WM (March 1998). "DNA double-
stranded breaks induce histone H2AX
phosphorylation on serine 139" (https://do
i.org/10.1074%2Fjbc.273.10.5858) . The
Journal of Biological Chemistry. 273 (10):
5858–68. doi:10.1074/jbc.273.10.5858 (ht
tps://doi.org/10.1074%2Fjbc.273.10.585
8) . PMID 9488723 (https://pubmed.ncbi.
nlm.nih.gov/9488723) .
49. Mailand N, Bekker-Jensen S, Faustrup H,
Melander F, Bartek J, Lukas C, Lukas J
(November 2007). "RNF8 ubiquitylates
histones at DNA double-strand breaks and
promotes assembly of repair proteins" (htt
ps://doi.org/10.1016%2Fj.cell.2007.09.04
0) . Cell. 131 (5): 887–900.
doi:10.1016/j.cell.2007.09.040 (https://do
i.org/10.1016%2Fj.cell.2007.09.040) .
m.nih.gov/18001824) . S2CID 14232192
D:14232192) .
50. Luijsterburg MS, Acs K, Ackermann L,
Wiegant WW, Bekker-Jensen S, Larsen DH,
et al. (May 2012). "A new non-catalytic role
for ubiquitin ligase RNF8 in unfolding
higher-order chromatin structure" (https://
3365417) . The EMBO Journal. 31 (11):
2511–27. doi:10.1038/emboj.2012.104 (h
ttps://doi.org/10.1038%2Femboj.2012.10
m.nih.gov/22531782) .
51. Luijsterburg MS, Goedhart J, Moser J,
Kool H, Geverts B, Houtsmuller AB, et al.
(August 2007). "Dynamic in vivo
interaction of DDB2 E3 ubiquitin ligase
with UV-damaged DNA is independent of
damage-recognition protein XPC" (https://
doi.org/10.1242%2Fjcs.008367) . Journal
of Cell Science. 120 (Pt 15): 2706–16.
doi:10.1242/jcs.008367 (https://doi.org/1
0.1242%2Fjcs.008367) . PMID 17635991
991) .
52. Pines A, Vrouwe MG, Marteijn JA, Typas D,
Luijsterburg MS, Cansoy M, et al. (October
2012). "PARP1 promotes nucleotide
excision repair through DDB2 stabilization
and recruitment of ALC1" (https://www.nc
bi.nlm.nih.gov/pmc/articles/PMC347122
3) . The Journal of Cell Biology. 199 (2):
235–49. doi:10.1083/jcb.201112132 (http
s://doi.org/10.1083%2Fjcb.201112132) .
m.nih.gov/23045548) .
53. Jazayeri A, Falck J, Lukas C, Bartek J,
Smith GC, Lukas J, Jackson SP (January
2006). "ATM- and cell cycle-dependent
regulation of ATR in response to DNA
double-strand breaks". Nature Cell
Biology. 8 (1): 37–45.
doi:10.1038/ncb1337 (https://doi.org/10.1
038%2Fncb1337) . PMID 16327781 (http
S2CID 9797133 (https://api.semanticscho
lar.org/CorpusID:9797133) .
54. Bakkenist CJ, Kastan MB (January 2003).
"DNA damage activates ATM through
intermolecular autophosphorylation and
dimer dissociation". Nature. 421 (6922):
499–506. Bibcode:2003Natur.421..499B
(https://ui.adsabs.harvard.edu/abs/2003N
atur.421..499B) .
doi:10.1038/nature01368 (https://doi.org/
10.1038%2Fnature01368) .
m.nih.gov/12556884) . S2CID 4403303 (h
403303) .
55. Wei Q, Li L, Chen D (2007). DNA Repair,
Genetic Instability, and Cancer. World
Scientific. ISBN 978-981-270-014-8.
56. Schonthal AH (2004). Checkpoint Controls
and Cancer (https://archive.org/details/ch
eckpointcontro00axel_0) . Humana Press.
ISBN 978-1-58829-500-2.
57. Gartel AL, Tyner AL (June 2002). "The role
of the cyclin-dependent kinase inhibitor
p21 in apoptosis" (http://mct.aacrjournals.
org/cgi/pmidlookup?view=long&pmid=12
479224) . Molecular Cancer Therapeutics.
1 (8): 639–49. PMID 12479224 (https://pu
58. Janion C (2001). "Some aspects of the
SOS response system--a critical survey" (h
ttps://doi.org/10.18388%2Fabp.2001_38
94) . Acta Biochimica Polonica. 48 (3):
599–610. doi:10.18388/abp.2001_3894 (h
ttps://doi.org/10.18388%2Fabp.2001_38
94) . PMID 11833768 (https://pubmed.nc
bi.nlm.nih.gov/11833768) .
59. Erill I, Campoy S, Barbé J (November
2007). "Aeons of distress: an evolutionary
perspective on the bacterial SOS
response" (https://doi.org/10.1111%2Fj.1
574-6976.2007.00082.x) . FEMS
Microbiology Reviews. 31 (6): 637–56.
doi:10.1111/j.1574-6976.2007.00082.x (ht
tps://doi.org/10.1111%2Fj.1574-6976.200
7.00082.x) . PMID 17883408 (https://pub
med.ncbi.nlm.nih.gov/17883408) .
60. Schlacher K, Pham P, Cox MM, Goodman
MF (February 2006). "Roles of DNA
polymerase V and RecA protein in SOS
damage-induced mutation". Chemical
Reviews. 106 (2): 406–19.
doi:10.1021/cr0404951 (https://doi.org/1
0.1021%2Fcr0404951) . PMID 16464012
012) .
61. Fry RC, Begley TJ, Samson LD (2004).
"Genome-wide responses to DNA-
damaging agents". Annual Review of
Microbiology. 59: 357–77.
doi:10.1146/annurev.micro.59.031805.13
3658 (https://doi.org/10.1146%2Fannurev.
micro.59.031805.133658) .
m.nih.gov/16153173) .
62. Espejel S, Martín M, Klatt P, Martín-
Caballero J, Flores JM, Blasco MA (May
2004). "Shorter telomeres, accelerated
ageing and increased lymphoma in DNA-
PKcs-deficient mice" (https://www.ncbi.nl
m.nih.gov/pmc/articles/PMC1299048) .
EMBO Reports. 5 (5): 503–09.
doi:10.1038/sj.embor.7400127 (https://do
i.org/10.1038%2Fsj.embor.7400127) .
m.nih.gov/15105825) .
63. de Boer J, Andressoo JO, de Wit J,
Huijmans J, Beems RB, van Steeg H, et al.
(May 2002). "Premature aging in mice
deficient in DNA repair and transcription".
Science. 296 (5571): 1276–79.
Bibcode:2002Sci...296.1276D (https://ui.a
dsabs.harvard.edu/abs/2002Sci...296.12
76D) . doi:10.1126/science.1070174 (http
s://doi.org/10.1126%2Fscience.1070174)
. PMID 11950998 (https://pubmed.ncbi.nl
m.nih.gov/11950998) . S2CID 41930529
D:41930529) .
64. Dollé ME, Busuttil RA, Garcia AM,
Wijnhoven S, van Drunen E, Niedernhofer
LJ, et al. (April 2006). "Increased genomic
instability is not a prerequisite for
shortened lifespan in DNA repair deficient
mice". Mutation Research. 596 (1–2): 22–
35. doi:10.1016/j.mrfmmm.2005.11.008
(https://doi.org/10.1016%2Fj.mrfmmm.20
05.11.008) . PMID 16472827 (https://pub
65. Kobayashi Y, Narumi I, Satoh K, Funayama
T, Kikuchi M, Kitayama S, Watanabe H
(November 2004). "Radiation response
mechanisms of the extremely
radioresistant bacterium Deinococcus
radiodurans". Uchu Seibutsu Kagaku. 18
(3): 134–35. PMID 15858357 (https://pub
66. Spindler SR (September 2005). "Rapid and
reversible induction of the longevity,
anticancer and genomic effects of caloric
restriction". Mechanisms of Ageing and
Development. 126 (9): 960–66.
doi:10.1016/j.mad.2005.03.016 (https://d
oi.org/10.1016%2Fj.mad.2005.03.016) .
m.nih.gov/15927235) . S2CID 7067036 (h
067036) .
67. Halicka HD, Zhao H, Li J, Lee YS, Hsieh TC,
Wu JM, Darzynkiewicz Z (December
2012). "Potential anti-aging agents
suppress the level of constitutive mTOR-
and DNA damage- signaling" (https://ww
w.ncbi.nlm.nih.gov/pmc/articles/PMC361
5161) . Aging. 4 (12): 952–65.
doi:10.18632/aging.100521 (https://doi.or
g/10.18632%2Faging.100521) .
m.nih.gov/23363784) .
68. Tissenbaum HA, Guarente L (March
2001). "Increased dosage of a sir-2 gene
extends lifespan in Caenorhabditis
elegans". Nature. 410 (6825): 227–30.
Bibcode:2001Natur.410..227T (https://ui.a
27T) . doi:10.1038/35065638 (https://doi.
org/10.1038%2F35065638) .
m.nih.gov/11242085) . S2CID 4356885 (h
356885) .
69. Cohen HY, Miller C, Bitterman KJ, Wall NR,
Hekking B, Kessler B, et al. (July 2004).
"Calorie restriction promotes mammalian
cell survival by inducing the SIRT1
deacetylase". Science. 305 (5682): 390–
92. Bibcode:2004Sci...305..390C (https://u
i.adsabs.harvard.edu/abs/2004Sci...305..
390C) . doi:10.1126/science.1099196 (htt
ps://doi.org/10.1126%2Fscience.109919
i.nlm.nih.gov/15205477) .
70. Cabelof DC, Yanamadala S, Raffoul JJ,
Guo Z, Soofi A, Heydari AR (March 2003).
"Caloric restriction promotes genomic
stability by induction of base excision
repair and reversal of its age-related
decline". DNA Repair. 2 (3): 295–307.
doi:10.1016/S1568-7864(02)00219-7 (http
s://doi.org/10.1016%2FS1568-7864%280
2%2900219-7) . PMID 12547392 (https://
71. Stuart JA, Karahalil B, Hogue BA, Souza-
Pinto NC, Bohr VA (March 2004).
"Mitochondrial and nuclear DNA base
excision repair are affected differently by
caloric restriction" (https://zenodo.org/rec
ord/1236076) . FASEB Journal. 18 (3):
595–97. doi:10.1096/fj.03-0890fje (http
s://doi.org/10.1096%2Ffj.03-0890fje) .
m.nih.gov/14734635) . S2CID 43118901
D:43118901) .
72. Walker DW, McColl G, Jenkins NL, Harris J,
Lithgow GJ (May 2000). "Evolution of
lifespan in C. elegans". Nature. 405
(6784): 296–97. doi:10.1038/35012693 (h
ttps://doi.org/10.1038%2F35012693) .
m.nih.gov/10830948) . S2CID 4402039 (h
402039) .
73. Johnson G (28 December 2010).
"Unearthing Prehistoric Tumors, and
Debate" (https://www.nytimes.com/2010/
12/28/health/28cancer.html) . The New
York Times. "If we lived long enough,
sooner or later we all would get cancer."
74. Alberts B, Johnson A, Lewis J, et al.
(2002). "The Preventable Causes of
Cancer" (https://www.ncbi.nlm.nih.gov/bo
oks/NBK26897/) . Molecular biology of
the cell (4th ed.). New York: Garland
Science. ISBN 978-0-8153-4072-0. "A
certain irreducible background incidence
of cancer is to be expected regardless of
circumstances: mutations can never be
absolutely avoided, because they are an
inescapable consequence of fundamental
limitations on the accuracy of DNA
replication, as discussed in Chapter 5. If a
human could live long enough, it is
inevitable that at least one of his or her
cells would eventually accumulate a set of
mutations sufficient for cancer to
develop."
75. Friedenson B (August 2007). "The
BRCA1/2 pathway prevents hematologic
cancers in addition to breast and ovarian
cancers" (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC1959234) . BMC Cancer.
7: 152. doi:10.1186/1471-2407-7-152 (http
s://doi.org/10.1186%2F1471-2407-7-
152) . PMC 1959234 (https://www.ncbi.nl
m.nih.gov/17683622) .
76. Gavande NS, VanderVere-Carozza PS,
Hinshaw HD, Jalal SI, Sears CR, Pawelczak
KS, Turchi JJ (April 2016). "DNA repair
targeted therapy: The past or future of
cancer treatment?" (https://www.ncbi.nlm.
Pharmacology & Therapeutics. 160: 65–
83. doi:10.1016/j.pharmthera.2016.02.003
(https://doi.org/10.1016%2Fj.pharmthera.
2016.02.003) . PMC 4811676 (https://ww
1676) . PMID 26896565 (https://pubmed.
77. Bryant HE, Schultz N, Thomas HD, Parker
KM, Flower D, Lopez E, et al. (April 2005).
"Specific killing of BRCA2-deficient
tumours with inhibitors of poly(ADP-
ribose) polymerase". Nature. 434 (7035):
913–17. Bibcode:2005Natur.434..913B (ht
tps://ui.adsabs.harvard.edu/abs/2005Nat
ur.434..913B) . doi:10.1038/nature03443
(https://doi.org/10.1038%2Fnature0344
i.nlm.nih.gov/15829966) . S2CID 4391043
D:4391043) .
78. Goldstein M, Kastan MB (2015). "The DNA
damage response: implications for tumor
responses to radiation and
chemotherapy". Annual Review of
Medicine. 66: 129–43.
doi:10.1146/annurev-med-081313-121208
(https://doi.org/10.1146%2Fannurev-med-
081313-121208) . PMID 25423595 (http
79. Jeggo PA, Pearl LH, Carr AM (January
2016). "DNA repair, genome stability and
cancer: a historical perspective" (http://sr
o.sussex.ac.uk/59275/1/29783_0_merge
d_1440861060.pdf) (PDF). Nature
Reviews. Cancer. 16 (1): 35–42.
doi:10.1038/nrc.2015.4 (https://doi.org/1
0.1038%2Fnrc.2015.4) . PMID 26667849
849) . S2CID 14941857 (https://api.sema
nticscholar.org/CorpusID:14941857) .
80. Bartkova J, Horejsí Z, Koed K, Krämer A,
Tort F, Zieger K, et al. (April 2005). "DNA
damage response as a candidate anti-
cancer barrier in early human
tumorigenesis". Nature. 434 (7035): 864–
70. Bibcode:2005Natur.434..864B (https://
ui.adsabs.harvard.edu/abs/2005Natur.43
4..864B) . doi:10.1038/nature03482 (http
s://doi.org/10.1038%2Fnature03482) .
m.nih.gov/15829956) . S2CID 4398393 (h
398393) .
81. Bartkova J, Rezaei N, Liontos M,
Karakaidos P, Kletsas D, Issaeva N, et al.
(November 2006). "Oncogene-induced
senescence is part of the tumorigenesis
barrier imposed by DNA damage
checkpoints". Nature. 444 (7119): 633–37.
Bibcode:2006Natur.444..633B (https://ui.a
33B) . doi:10.1038/nature05268 (https://d
oi.org/10.1038%2Fnature05268) .
m.nih.gov/17136093) . S2CID 4406956 (h
406956) .
82. Gaillard H, García-Muse T, Aguilera A (May
2015). "Replication stress and cancer".
Nature Reviews. Cancer. 15 (5): 276–89.
doi:10.1038/nrc3916 (https://doi.org/10.1
038%2Fnrc3916) . hdl:10261/123721 (htt
ps://hdl.handle.net/10261%2F123721) .
m.nih.gov/25907220) . S2CID 11342123
D:11342123) .
83. Halazonetis TD, Gorgoulis VG, Bartek J
(March 2008). "An oncogene-induced DNA
damage model for cancer development".
Science. 319 (5868): 1352–55.
Bibcode:2008Sci...319.1352H (https://ui.a
dsabs.harvard.edu/abs/2008Sci...319.13
52H) . doi:10.1126/science.1140735 (http
s://doi.org/10.1126%2Fscience.1140735)
. PMID 18323444 (https://pubmed.ncbi.nl
m.nih.gov/18323444) . S2CID 16426080
D:16426080) .
84. de Boer J, Hoeijmakers JH (March 2000).
"Nucleotide excision repair and human
syndromes" (https://repub.eur.nl/pub/316
6/eur_hoeijmakers_9074.pdf) (PDF).
Carcinogenesis. 21 (3): 453–60.
doi:10.1093/carcin/21.3.453 (https://doi.o
rg/10.1093%2Fcarcin%2F21.3.453) .
m.nih.gov/10688865) .
85. Broustas CG, Lieberman HB (February
2014). "DNA damage response genes and
the development of cancer metastasis" (ht
tps://www.ncbi.nlm.nih.gov/pmc/articles/
PMC4064942) . Radiation Research. 181
(2): 111–30.
Bibcode:2014RadR..181..111B (https://ui.
adsabs.harvard.edu/abs/2014RadR..181..
111B) . doi:10.1667/RR13515.1 (https://d
oi.org/10.1667%2FRR13515.1) .
m.nih.gov/24397478) .
86. Zhang P, Wang J, Gao W, Yuan BZ, Rogers
J, Reed E (May 2004). "CHK2 kinase
expression is down-regulated due to
promoter methylation in non-small cell
lung cancer" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC419366) . Molecular
Cancer. 3 (4): 14. doi:10.1186/1476-4598-
3-14 (https://doi.org/10.1186%2F1476-45
98-3-14) . PMC 419366 (https://www.ncbi.
m.nih.gov/15125777) .
87. Baylin SB, Ohm JE (February 2006).
"Epigenetic gene silencing in cancer – a
mechanism for early oncogenic pathway
addiction?". Nature Reviews. Cancer. 6 (2):
107–16. doi:10.1038/nrc1799 (https://doi.
org/10.1038%2Fnrc1799) .
m.nih.gov/16491070) . S2CID 2514545 (h
514545) .
88. Kanwal R, Gupta S (April 2012).
"Epigenetic modifications in cancer" (http
MC3590802) . Clinical Genetics. 81 (4):
303–11. doi:10.1111/j.1399-
0004.2011.01809.x (https://doi.org/10.11
11%2Fj.1399-0004.2011.01809.x) .
m.nih.gov/22082348) .
89. Baldassarre G, Battista S, Belletti B,
Thakur S, Pentimalli F, Trapasso F, et al.
(April 2003). "Negative regulation of
BRCA1 gene expression by HMGA1
proteins accounts for the reduced BRCA1
protein levels in sporadic breast
carcinoma" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC150734) . Molecular
and Cellular Biology. 23 (7): 2225–38.
doi:10.1128/MCB.23.7.2225-2238.2003 (h
ttps://doi.org/10.1128%2FMCB.23.7.2225-
2238.2003) . PMC 150734 (https://www.n
cbi.nlm.nih.gov/pmc/articles/PMC15073
90. Jacinto FV, Esteller M (July 2007).
"Mutator pathways unleashed by
epigenetic silencing in human cancer" (htt
ps://doi.org/10.1093%2Fmutage%2Fgem
009) . Mutagenesis. 22 (4): 247–53.
doi:10.1093/mutage/gem009 (https://doi.
org/10.1093%2Fmutage%2Fgem009) .
m.nih.gov/17412712) .
91. Lahtz C, Pfeifer GP (February 2011).
"Epigenetic changes of DNA repair genes
in cancer" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3030973) . Journal of
Molecular Cell Biology. 3 (1): 51–58.
doi:10.1093/jmcb/mjq053 (https://doi.or
g/10.1093%2Fjmcb%2Fmjq053) .
m.nih.gov/21278452) . Epigenetic
changes of DNA repair genes in cancer (ht
tps://web.archive.org/web/201510161615
04/http://jmcb.oxfordjournals.org/conten
t/3/1/51.long)
92. Bernstein C, Nfonsam V, Prasad AR,
Bernstein H (March 2013). "Epigenetic
field defects in progression to cancer" (htt
ps://www.ncbi.nlm.nih.gov/pmc/articles/
PMC3648662) . World Journal of
Gastrointestinal Oncology. 5 (3): 43–49.
doi:10.4251/wjgo.v5.i3.43 (https://doi.or
g/10.4251%2Fwjgo.v5.i3.43) .
m.nih.gov/23671730) .
93. Narayanan L, Fritzell JA, Baker SM, Liskay
RM, Glazer PM (April 1997). "Elevated
levels of mutation in multiple tissues of
mice deficient in the DNA mismatch repair
gene Pms2" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC20332) . Proceedings
of the National Academy of Sciences of
the United States of America. 94 (7):
3122–27. Bibcode:1997PNAS...94.3122N
(https://ui.adsabs.harvard.edu/abs/1997P
NAS...94.3122N) .
doi:10.1073/pnas.94.7.3122 (https://doi.o
rg/10.1073%2Fpnas.94.7.3122) .
PMC 20332 (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC20332) .
nih.gov/9096356) .
94. Hegan DC, Narayanan L, Jirik FR,
Edelmann W, Liskay RM, Glazer PM
(December 2006). "Differing patterns of
genetic instability in mice deficient in the
mismatch repair genes Pms2, Mlh1, Msh2,
Msh3 and Msh6" (https://www.ncbi.nlm.ni
Carcinogenesis. 27 (12): 2402–08.
doi:10.1093/carcin/bgl079 (https://doi.or
g/10.1093%2Fcarcin%2Fbgl079) .
m.nih.gov/16728433) .
95. Tutt AN, van Oostrom CT, Ross GM, van
Steeg H, Ashworth A (March 2002).
"Disruption of Brca2 increases the
spontaneous mutation rate in vivo:
synergism with ionizing radiation" (https://
1084010) . EMBO Reports. 3 (3): 255–60.
doi:10.1093/embo-reports/kvf037 (http
s://doi.org/10.1093%2Fembo-reports%2Fk
vf037) . PMC 1084010 (https://www.ncbi.
m.nih.gov/11850397) .
96. German J (March 1969). "Bloom's
syndrome. I. Genetical and clinical
observations in the first twenty-seven
patients" (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC1706430) . American
Journal of Human Genetics. 21 (2): 196–
227. PMC 1706430 (https://www.ncbi.nl
nih.gov/5770175) .
97. O'Hagan HM, Mohammad HP, Baylin SB
(August 2008). "Double strand breaks can
initiate gene silencing and SIRT1-
dependent onset of DNA methylation in an
exogenous promoter CpG island" (https://
2491723) . PLOS Genetics. 4 (8):
e1000155.
doi:10.1371/journal.pgen.1000155 (http
s://doi.org/10.1371%2Fjournal.pgen.100
m.nih.gov/18704159) .
98. Cuozzo C, Porcellini A, Angrisano T,
Morano A, Lee B, Di Pardo A, et al. (July
2007). "DNA damage, homology-directed
repair, and DNA methylation" (https://ww
3100) . PLOS Genetics. 3 (7): e110.
m.nih.gov/17616978) .
99. Malkin D (April 2011). "Li-fraumeni
syndrome" (https://www.ncbi.nlm.nih.gov/
pmc/articles/PMC3135649) . Genes &
Cancer. 2 (4): 475–84.
doi:10.1177/1947601911413466 (https://
doi.org/10.1177%2F1947601911413466)
. PMC 3135649 (https://www.ncbi.nlm.nih.
m.nih.gov/21779515) .
100. Fearon ER (November 1997). "Human
cancer syndromes: clues to the origin and
nature of cancer". Science. 278 (5340):
1043–50. Bibcode:1997Sci...278.1043F (h
ttps://ui.adsabs.harvard.edu/abs/1997Sc
i...278.1043F) .
doi:10.1126/science.278.5340.1043 (http
s://doi.org/10.1126%2Fscience.278.5340.
1043) . PMID 9353177 (https://pubmed.n
cbi.nlm.nih.gov/9353177) .
101. Halford S, Rowan A, Sawyer E, Talbot I,
Tomlinson I (June 2005). "O(6)-
methylguanine methyltransferase in
colorectal cancers: detection of
mutations, loss of expression, and weak
association with G:C>A:T transitions" (http
MC1774551) . Gut. 54 (6): 797–802.
doi:10.1136/gut.2004.059535 (https://doi.
org/10.1136%2Fgut.2004.059535) .
m.nih.gov/15888787) .
102. Shen L, Kondo Y, Rosner GL, Xiao L,
Hernandez NS, Vilaythong J, et al.
(September 2005). "MGMT promoter
methylation and field defect in sporadic
colorectal cancer" (https://doi.org/10.109
3%2Fjnci%2Fdji275) . Journal of the
National Cancer Institute. 97 (18): 1330–
38. doi:10.1093/jnci/dji275 (https://doi.or
g/10.1093%2Fjnci%2Fdji275) .
m.nih.gov/16174854) .
103. Psofaki V, Kalogera C, Tzambouras N,
Stephanou D, Tsianos E, Seferiadis K,
Kolios G (July 2010). "Promoter
methylation status of hMLH1, MGMT, and
CDKN2A/p16 in colorectal adenomas" (htt
ps://www.ncbi.nlm.nih.gov/pmc/articles/
PMC2909555) . World Journal of
Gastroenterology. 16 (28): 3553–60.
doi:10.3748/wjg.v16.i28.3553 (https://doi.
org/10.3748%2Fwjg.v16.i28.3553) .
m.nih.gov/20653064) .
104. Lee KH, Lee JS, Nam JH, Choi C, Lee MC,
Park CS, et al. (October 2011). "Promoter
methylation status of hMLH1, hMSH2, and
MGMT genes in colorectal cancer
associated with adenoma-carcinoma
sequence". Langenbeck's Archives of
Surgery. 396 (7): 1017–26.
doi:10.1007/s00423-011-0812-9 (https://d
oi.org/10.1007%2Fs00423-011-0812-9) .
m.nih.gov/21706233) . S2CID 8069716 (h
069716) .
105. Amatu A, Sartore-Bianchi A, Moutinho C,
Belotti A, Bencardino K, Chirico G, et al.
(April 2013). "Promoter CpG island
hypermethylation of the DNA repair
enzyme MGMT predicts clinical response
to dacarbazine in a phase II study for
metastatic colorectal cancer" (https://doi.
org/10.1158%2F1078-0432.CCR-12-351
8) . Clinical Cancer Research. 19 (8):
2265–72. doi:10.1158/1078-0432.CCR-12-
3518 (https://doi.org/10.1158%2F1078-04
32.CCR-12-3518) . PMID 23422094 (http
106. Mokarram P, Zamani M, Kavousipour S,
Naghibalhossaini F, Irajie C, Moradi Sarabi
M, Hosseini SV (May 2013). "Different
patterns of DNA methylation of the two
distinct O6-methylguanine-DNA
methyltransferase (O6-MGMT) promoter
regions in colorectal cancer". Molecular
Biology Reports. 40 (5): 3851–57.
doi:10.1007/s11033-012-2465-3 (https://d
oi.org/10.1007%2Fs11033-012-2465-3) .
m.nih.gov/23271133) . S2CID 18733871
D:18733871) .
107. Truninger K, Menigatti M, Luz J, Russell A,
Haider R, Gebbers JO, et al. (May 2005).
"Immunohistochemical analysis reveals
high frequency of PMS2 defects in
colorectal cancer". Gastroenterology. 128
(5): 1160–71.
doi:10.1053/j.gastro.2005.01.056 (https://
doi.org/10.1053%2Fj.gastro.2005.01.05
108. Valeri N, Gasparini P, Fabbri M, Braconi C,
Veronese A, Lovat F, et al. (April 2010).
"Modulation of mismatch repair and
genomic stability by miR-155" (https://ww
2463) . Proceedings of the National
Academy of Sciences of the United States
of America. 107 (15): 6982–87.
Bibcode:2010PNAS..107.6982V (https://u
i.adsabs.harvard.edu/abs/2010PNAS..10
7.6982V) . doi:10.1073/pnas.1002472107
(https://doi.org/10.1073%2Fpnas.100247
m.nih.gov/20351277) .
109. Facista A, Nguyen H, Lewis C, Prasad AR,
Ramsey L, Zaitlin B, et al. (April 2012).
"Deficient expression of DNA repair
enzymes in early progression to sporadic
colon cancer" (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC3351028) . Genome
Integrity. 3 (1): 3. doi:10.1186/2041-9414-
3-3 (https://doi.org/10.1186%2F2041-941
4-3-3) . PMC 3351028 (https://www.ncbi.n
m.nih.gov/22494821) .
110. Human DNA Repair Genes (http://science
park.mdanderson.org/labs/wood/dna_rep
air_genes.html) , 15 April 2014, MD
Anderson Cancer Center, University of
Texas
111. Jin B, Robertson KD (2013). "DNA
methyltransferases, DNA damage repair,
and cancer" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC3707278) . Advances
in Experimental Medicine and Biology.
754: 3–29. doi:10.1007/978-1-4419-9967-
2_1 (https://doi.org/10.1007%2F978-1-44
19-9967-2_1) . ISBN 978-1-4419-9966-5.
m.nih.gov/22956494) .
112. Krishnan K, Steptoe AL, Martin HC, Wani S,
Nones K, Waddell N, et al. (February
2013). "MicroRNA-182-5p targets a
network of genes involved in DNA repair"
es/PMC3543090) . RNA. 19 (2): 230–42.
doi:10.1261/rna.034926.112 (https://doi.o
rg/10.1261%2Frna.034926.112) .
m.nih.gov/23249749) .
113. Chaisaingmongkol J, Popanda O, Warta R,
Dyckhoff G, Herpel E, Geiselhart L, et al.
(December 2012). "Epigenetic screen of
human DNA repair genes identifies
aberrant promoter methylation of NEIL1 in
head and neck squamous cell carcinoma"
(https://doi.org/10.1038%2Fonc.2011.66
0) . Oncogene. 31 (49): 5108–16.
doi:10.1038/onc.2011.660 (https://doi.or
g/10.1038%2Fonc.2011.660) .
m.nih.gov/22286769) .
114. Singh P, Yang M, Dai H, Yu D, Huang Q, Tan
W, et al. (November 2008).
"Overexpression and hypomethylation of
flap endonuclease 1 gene in breast and
other cancers" (https://www.ncbi.nlm.nih.
Molecular Cancer Research. 6 (11): 1710–
17. doi:10.1158/1541-7786.MCR-08-0269
(https://doi.org/10.1158%2F1541-7786.M
CR-08-0269) . PMC 2948671 (https://ww
8671) . PMID 19010819 (https://pubmed.
115. Lam JS, Seligson DB, Yu H, Li A, Eeva M,
Pantuck AJ, et al. (August 2006). "Flap
endonuclease 1 is overexpressed in
prostate cancer and is associated with a
high Gleason score". BJU International. 98
(2): 445–51. doi:10.1111/j.1464-
410X.2006.06224.x (https://doi.org/10.11
11%2Fj.1464-410X.2006.06224.x) .
m.nih.gov/16879693) . S2CID 22165252
D:22165252) .
116. Kim JM, Sohn HY, Yoon SY, Oh JH, Yang
JO, Kim JH, et al. (January 2005).
"Identification of gastric cancer-related
genes using a cDNA microarray
containing novel expressed sequence tags
expressed in gastric cancer cells" (https://
doi.org/10.1158%2F1078-
0432.473.11.2) . Clinical Cancer
Research. 11 (2 Pt 1): 473–82.
doi:10.1158/1078-0432.473.11.2 (https://
doi.org/10.1158%2F1078-
0432.473.11.2) . PMID 15701830 (https://
117. Wang K, Xie C, Chen D (May 2014). "Flap
endonuclease 1 is a promising candidate
biomarker in gastric cancer and is
involved in cell proliferation and
apoptosis" (https://doi.org/10.3892%2Fij
mm.2014.1682) . International Journal of
Molecular Medicine. 33 (5): 1268–74.
doi:10.3892/ijmm.2014.1682 (https://doi.
org/10.3892%2Fijmm.2014.1682) .
m.nih.gov/24590400) .
118. Krause A, Combaret V, Iacono I, Lacroix B,
Compagnon C, Bergeron C, et al. (July
2005). "Genome-wide analysis of gene
expression in neuroblastomas detected by
mass screening" (https://hal.archives-ouv
ertes.fr/hal-00157917/file/Cancer_Letters
_2004.pdf) (PDF). Cancer Letters. 225 (1):
111–20. doi:10.1016/j.canlet.2004.10.035
(https://doi.org/10.1016%2Fj.canlet.2004.
10.035) . PMID 15922863 (https://pubme
119. Iacobuzio-Donahue CA, Maitra A, Olsen M,
Lowe AW, van Heek NT, Rosty C, et al.
(April 2003). "Exploration of global gene
expression patterns in pancreatic
adenocarcinoma using cDNA microarrays"
es/PMC1851213) . The American Journal
of Pathology. 162 (4): 1151–62.
doi:10.1016/S0002-9440(10)63911-9 (http
s://doi.org/10.1016%2FS0002-9440%281
0%2963911-9) . PMC 1851213 (https://w
51213) . PMID 12651607 (https://pubme
120. Sato M, Girard L, Sekine I, Sunaga N,
Ramirez RD, Kamibayashi C, Minna JD
(October 2003). "Increased expression
and no mutation of the Flap endonuclease
(FEN1) gene in human lung cancer" (http
s://doi.org/10.1038%2Fsj.onc.1206977) .
Oncogene. 22 (46): 7243–46.
doi:10.1038/sj.onc.1206977 (https://doi.o
rg/10.1038%2Fsj.onc.1206977) .
m.nih.gov/14562054) .
121. Bi FF, Li D, Yang Q (2013).
"Hypomethylation of ETS transcription
factor binding sites and upregulation of
PARP1 expression in endometrial cancer"
es/PMC3666359) . BioMed Research
International. 2013: 946268.
doi:10.1155/2013/946268 (https://doi.or
g/10.1155%2F2013%2F946268) .
m.nih.gov/23762867) .
122. Bi FF, Li D, Yang Q (February 2013).
"Promoter hypomethylation, especially
around the E26 transformation-specific
motif, and increased expression of poly
(ADP-ribose) polymerase 1 in BRCA-
mutated serous ovarian cancer" (https://w
99366) . BMC Cancer. 13: 90.
doi:10.1186/1471-2407-13-90 (https://doi.
org/10.1186%2F1471-2407-13-90) .
m.nih.gov/23442605) .
123. Supek F, Lehner B (May 2015). "Differential
DNA mismatch repair underlies mutation
rate variation across the human genome"
es/PMC4425546) . Nature. 521 (7550):
81–84. Bibcode:2015Natur.521...81S (http
s://ui.adsabs.harvard.edu/abs/2015Natur.
521...81S) . doi:10.1038/nature14173 (htt
ps://doi.org/10.1038%2Fnature14173) .
m.nih.gov/25707793) .
124. Zheng CL, Wang NJ, Chung J, Moslehi H,
Sanborn JZ, Hur JS, et al. (November
2014). "Transcription restores DNA repair
to heterochromatin, determining regional
mutation rates in cancer genomes" (http
MC4254608) . Cell Reports. 9 (4): 1228–
34. doi:10.1016/j.celrep.2014.10.031 (http
s://doi.org/10.1016%2Fj.celrep.2014.10.0
m.nih.gov/25456125) .
125. Li F, Mao G, Tong D, Huang J, Gu L, Yang
W, Li GM (April 2013). "The histone mark
H3K36me3 regulates human DNA
mismatch repair through its interaction
with MutSα" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC3641580) . Cell. 153
(3): 590–600.
doi:10.1016/j.cell.2013.03.025 (https://do
i.org/10.1016%2Fj.cell.2013.03.025) .
m.nih.gov/23622243) .
126. Supek F, Lehner B (July 2017). "Clustered
Mutation Signatures Reveal that Error-
Prone DNA Repair Targets Mutations to
Active Genes" (https://doi.org/10.1016%2
Fj.cell.2017.07.003) . Cell. 170 (3): 534–
547.e23. doi:10.1016/j.cell.2017.07.003 (h
ttps://doi.org/10.1016%2Fj.cell.2017.07.0
03) . hdl:10230/35343 (https://hdl.handle.
net/10230%2F35343) . PMID 28753428
428) .
127. Polak P, Lawrence MS, Haugen E, Stoletzki
N, Stojanov P, Thurman RE, et al. (January
2014). "Reduced local mutation density in
regulatory DNA of cancer genomes is
linked to DNA repair" (https://www.ncbi.nl
Nature Biotechnology. 32 (1): 71–75.
doi:10.1038/nbt.2778 (https://doi.org/10.
1038%2Fnbt.2778) . PMC 4116484 (http
MC4116484) . PMID 24336318 (https://pu
128. Swenberg JA, Lu K, Moeller BC, Gao L,
Upton PB, Nakamura J, Starr TB (March
2011). "Endogenous versus exogenous
DNA adducts: their role in carcinogenesis,
epidemiology, and risk assessment" (http
MC3043087) . Toxicol Sci. 120 Suppl 1
(Suppl 1): S130–45.
doi:10.1093/toxsci/kfq371 (https://doi.or
g/10.1093%2Ftoxsci%2Fkfq371) .
m.nih.gov/21163908) .
129. Hamilton ML, Guo Z, Fuller CD, Van
Remmen H, Ward WF, Austad SN, Troyer
DA, Thompson I, Richardson A (May
2001). "A reliable assessment of 8-oxo-2-
deoxyguanosine levels in nuclear and
mitochondrial DNA using the sodium
iodide method to isolate DNA" (https://ww
450) . Nucleic Acids Res. 29 (10): 2117–
26. doi:10.1093/nar/29.10.2117 (https://d
oi.org/10.1093%2Fnar%2F29.10.2117) .
PMC 55450 (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC55450) .
m.nih.gov/11353081) .
130. Ming X, Matter B, Song M, Veliath E,
Shanley R, Jones R, Tretyakova N (March
2014). "Mapping structurally defined
guanine oxidation products along DNA
duplexes: influence of local sequence
context and endogenous cytosine
methylation" (https://www.ncbi.nlm.nih.go
v/pmc/articles/PMC3985951) . J Am
Chem Soc. 136 (11): 4223–35.
doi:10.1021/ja411636j (https://doi.org/10.
1021%2Fja411636j) . PMC 3985951 (http
MC3985951) . PMID 24571128 (https://pu
131. Zhou X, Zhuang Z, Wang W, He L, Wu H,
Cao Y, Pan F, Zhao J, Hu Z, Sekhar C, Guo
Z (September 2016). "OGG1 is essential in
oxidative stress-induced DNA
demethylation". Cell Signal. 28 (9): 1163–
1171. doi:10.1016/j.cellsig.2016.05.021 (h
ttps://doi.org/10.1016%2Fj.cellsig.2016.0
132. Poetsch AR (2020). "The genomics of
oxidative DNA damage, repair, and
resulting mutagenesis" (https://www.ncbi.
Comput Struct Biotechnol J. 18: 207–219.
doi:10.1016/j.csbj.2019.12.013 (https://do
i.org/10.1016%2Fj.csbj.2019.12.013) .
m.nih.gov/31993111) .
133. D'Augustin O, Huet S, Campalans A,
Radicella JP (November 2020). "Lost in
the Crowd: How Does Human 8-
Oxoguanine DNA Glycosylase 1 (OGG1)
Find 8-Oxoguanine in the Genome?" (http
MC7664663) . Int J Mol Sci. 21 (21):
8360. doi:10.3390/ijms21218360 (https://
doi.org/10.3390%2Fijms21218360) .
m.nih.gov/33171795) .
134. Lan L, Nakajima S, Oohata Y, Takao M,
Okano S, Masutani M, Wilson SH, Yasui A
(September 2004). "In situ analysis of
repair processes for oxidative DNA
damage in mammalian cells" (https://ww
8826) . Proc Natl Acad Sci U S A. 101
(38): 13738–43.
Bibcode:2004PNAS..10113738L (https://u
i.adsabs.harvard.edu/abs/2004PNAS..101
13738L) . doi:10.1073/pnas.0406048101
(https://doi.org/10.1073%2Fpnas.040604
m.nih.gov/15365186) .
135. Maeder ML, Angstman JF, Richardson ME,
Linder SJ, Cascio VM, Tsai SQ, Ho QH,
Sander JD, Reyon D, Bernstein BE, Costello
JF, Wilkinson MF, Joung JK (December
2013). "Targeted DNA demethylation and
activation of endogenous genes using
programmable TALE-TET1 fusion
proteins" (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC3858462) . Nat.
Biotechnol. 31 (12): 1137–42.
doi:10.1038/nbt.2726 (https://doi.org/10.
1038%2Fnbt.2726) . PMC 3858462 (http
MC3858462) . PMID 24108092 (https://pu
136. Ding N, Bonham EM, Hannon BE, Amick
TR, Baylin SB, O'Hagan HM (June 2016).
"Mismatch repair proteins recruit DNA
methyltransferase 1 to sites of oxidative
DNA damage" (https://www.ncbi.nlm.nih.g
ov/pmc/articles/PMC4937888) . J Mol
Cell Biol. 8 (3): 244–54.
doi:10.1093/jmcb/mjv050 (https://doi.or
g/10.1093%2Fjmcb%2Fmjv050) .
m.nih.gov/26186941) .
137. Jiang Z, Lai Y, Beaver JM, Tsegay PS, Zhao
ML, Horton JK, Zamora M, Rein HL,
Miralles F, Shaver M, Hutcheson JD,
Agoulnik I, Wilson SH, Liu Y (January
2020). "Oxidative DNA Damage Modulates
DNA Methylation Pattern in Human Breast
Cancer 1 (BRCA1) Gene via the Crosstalk
between DNA Polymerase β and a de novo
DNA Methyltransferase" (https://www.ncb
i.nlm.nih.gov/pmc/articles/PMC701675
8) . Cells. 9 (1): 225.
doi:10.3390/cells9010225 (https://doi.or
g/10.3390%2Fcells9010225) .
m.nih.gov/31963223) .
138. Mortusewicz O, Schermelleh L, Walter J,
Cardoso MC, Leonhardt H (June 2005).
"Recruitment of DNA methyltransferase I
to DNA repair sites" (https://www.ncbi.nl
Proc Natl Acad Sci U S A. 102 (25): 8905–
9. Bibcode:2005PNAS..102.8905M (http
s://ui.adsabs.harvard.edu/abs/2005PNA
S..102.8905M) .
doi:10.1073/pnas.0501034102 (https://do
i.org/10.1073%2Fpnas.0501034102) .
m.nih.gov/15956212) .
139. Cuozzo C, Porcellini A, Angrisano T,
Morano A, Lee B, Di Pardo A, Messina S,
Iuliano R, Fusco A, Santillo MR, Muller MT,
Chiariotti L, Gottesman ME, Avvedimento
EV (July 2007). "DNA damage, homology-
directed repair, and DNA methylation" (http
MC1913100) . PLOS Genet. 3 (7): e110.
m.nih.gov/17616978) .
140. O'Hagan HM, Mohammad HP, Baylin SB
(August 2008). "Double strand breaks can
initiate gene silencing and SIRT1-
dependent onset of DNA methylation in an
exogenous promoter CpG island" (https://
2491723) . PLOS Genet. 4 (8): e1000155.
m.nih.gov/18704159) .
141. Ha K, Lee GE, Palii SS, Brown KD, Takeda Y,
Liu K, Bhalla KN, Robertson KD (January
2011). "Rapid and transient recruitment of
DNMT1 to DNA double-strand breaks is
mediated by its interaction with multiple
components of the DNA damage
response machinery" (https://www.ncbi.nl
Hum Mol Genet. 20 (1): 126–40.
doi:10.1093/hmg/ddq451 (https://doi.org/
10.1093%2Fhmg%2Fddq451) .
m.nih.gov/20940144) .
142. Russo G, Landi R, Pezone A, Morano A,
Zuchegna C, Romano A, Muller MT,
Gottesman ME, Porcellini A, Avvedimento
EV (September 2016). "DNA damage and
Repair Modify DNA methylation and
Chromatin Domain of the Targeted Locus:
Mechanism of allele methylation
polymorphism" (https://www.ncbi.nlm.nih.
gov/pmc/articles/PMC5024116) . Sci
Rep. 6: 33222.
Bibcode:2016NatSR...633222R (https://ui.
adsabs.harvard.edu/abs/2016NatSR...633
222R) . doi:10.1038/srep33222 (https://d
oi.org/10.1038%2Fsrep33222) .
m.nih.gov/27629060) .
143. Farris MH, Texter PA, Mora AA, Wiles MV,
Mac Garrigle EF, Klaus SA, Rosfjord K
(December 2020). "Detection of CRISPR-
mediated genome modifications through
altered methylation patterns of CpG
islands" (https://www.ncbi.nlm.nih.gov/p
mc/articles/PMC7709351) . BMC
Genomics. 21 (1): 856.
doi:10.1186/s12864-020-07233-2 (https://
doi.org/10.1186%2Fs12864-020-07233-
m.nih.gov/33267773) .
144. Allen B, Pezone A, Porcellini A, Muller MT,
Masternak MM (June 2017). "Non-
homologous end joining induced
alterations in DNA methylation: A source
of permanent epigenetic change" (https://
5522286) . Oncotarget. 8 (25): 40359–
40372. doi:10.18632/oncotarget.16122 (h
ttps://doi.org/10.18632%2Foncotarget.16
m.nih.gov/28423717) .
145. Cromie GA, Connelly JC, Leach DR
(December 2001). "Recombination at
double-strand breaks and DNA ends:
conserved mechanisms from phage to
humans" (https://doi.org/10.1016%2FS10
97-2765%2801%2900419-1) . Molecular
Cell. 8 (6): 1163–74. doi:10.1016/S1097-
2765(01)00419-1 (https://doi.org/10.101
6%2FS1097-2765%2801%2900419-1) .
m.nih.gov/11779493) .
146. O'Brien PJ (February 2006). "Catalytic
promiscuity and the divergent evolution of
DNA repair enzymes". Chemical Reviews.
106 (2): 720–52. doi:10.1021/cr040481v
(https://doi.org/10.1021%2Fcr040481v) .
m.nih.gov/16464022) .
147. Maresca B, Schwartz JH (January 2006).
"Sudden origins: a general mechanism of
evolution based on stress protein
concentration and rapid environmental
change" (https://doi.org/10.1002%2Far.b.2
0089) . The Anatomical Record Part B:
The New Anatomist. 289 (1): 38–46.
doi:10.1002/ar.b.20089 (https://doi.org/1
0.1002%2Far.b.20089) . PMID 16437551
551) .
148. "CRISPR gene-editing tool has scientists
thrilled – but nervous" (http://www.cbc.c
a/news/health/crispr-dna-gene-editing-1.3
339346) CBC news. Author Kelly Crowe.
30 November 2015.
External links
Media related to DNA repair at
Wikimedia Commons
Roswell Park Cancer Institute DNA
Repair Lectures (https://web.archive.or
g/web/20080825230122/http://asajj.ros
wellpark.org/huberman/DNA_Repair/DN
A_Repair.htm)
A comprehensive list of Human DNA
Repair Genes (https://web.archive.org/w
eb/20040724083244/http://www.cgal.ic
net.uk/DNA_Repair_Genes.html)
3D structures of some DNA repair
enzymes (https://web.archive.org/web/2
0080503033016/http://www.biochem.uc
l.ac.uk/bsm/xtal/teach/repair/tibs3.ht
ml)
Human DNA repair diseases (http://ww
w.scielo.br/scielo.php?pid=S0100-8455
1997000400032&script=sci_arttext&tln
g=en)
DNA repair special interest group (http
s://web.archive.org/web/200609282346
05/http://tango01.cit.nih.gov/sig/home.t
af?_function=main)
DNA Repair (http://users.rcn.com/jkimb
all.ma.ultranet/BiologyPages/D/DNArep
air.html) Archived (https://web.archive.
org/web/20180212073520/http://users.
rcn.com/jkimball.ma.ultranet/BiologyPa
ges/D/DNArepair.html) 12 February
2018 at the Wayback Machine
DNA Damage and DNA Repair (https://w
eb.archive.org/web/20100225121710/ht
tp://www.benbest.com/lifeext/aging.ht
ml#dna)
Segmental Progeria (https://web.archiv
e.org/web/20100225121710/http://ww
w.benbest.com/lifeext/aging.html#prog
eria)
DNA-damage repair; the good, the bad,
and the ugly (https://www.researchgate.
net/publication/5565866_DNA-damage_
repair_the_good_the_bad_and_the_ugl
y)
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DNA Repair - Wikipedia

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DNA repair is a collection of processes by

DNA damage resulting in multiple broken chromosomes

The rate of DNA repair is dependent on

1. an irreversible state of dormancy,

The DNA repair ability of a cell is vital to

The 2015 Nobel Prize in Chemistry was

The vast majority of DNA damage affects

DNA damage can be subdivided into two

1. endogenous damage such as attack

The replication of damaged DNA before

There are several types of damage to DNA

1. oxidation of bases [e.g. 8-oxo-7,8-

Damage caused by exogenous agents

1. UV-B light causes crosslinking

UV damage, alkylation/methylation, X-ray

Nuclear versus mitochondrial

In human cells, and eukaryotic cells in

Senescence and apoptosis

Senescence, an irreversible process in

It is important to distinguish between DNA

In contrast to DNA damage, a mutation is

Although distinctly different from each

Given these properties of DNA damage

Damage to DNA alters the spatial

Cells are known to eliminate three types of

1. Base excision repair (BER): damaged

The main double-strand break repair pathways

1. In NHEJ, DNA Ligase IV, a specialized

The extremophile Deinococcus

Topoisomerases introduce both single-

Another type of DNA double-strand breaks

Global response to DNA

The packaging of eukaryotic DNA into

Chromatin relaxation occurs rapidly at the

γH2AX, the phosphorylated form of H2AX

After rapid chromatin remodeling, cell

DNA damage checkpoints

DNA damage checkpoint is a signal

An important downstream target of ATM

The SOS response is the changes in gene

In Escherichia coli, SOS boxes are 20-

Eukaryotic cells exposed to DNA

In general global response to DNA damage

Pathological effects of poor DNA

DNA repair rate is an important determinant of cell pathology.

If the rate of DNA damage exceeds the

Longevity and caloric restriction

A number of individual genes have been

For example, increasing the gene dosage

The C. elegans gene AGE-1, an upstream

Hereditary DNA repair disorders

Defects in the NER mechanism are

Mental retardation often accompanies the

Other DNA repair disorders include:

Werner's syndrome: premature aging

Other diseases associated with reduced

Perhaps the most well-known of these

Many other drugs for use against other

DNA repair defects in cancer

It has become apparent over the past

Replication stress, along with the selection

The prevalence of DNA damage response