Base excision repair

Base excision repair (BER) is a cellular

mechanism, studied in the fields of
biochemistry and genetics, that repairs
damaged DNA throughout the cell cycle.
It is responsible primarily for removing
small, non-helix-distorting base lesions
from the genome. The related nucleotide
excision repair pathway repairs bulky
helix-distorting lesions. BER is important
for removing damaged bases that could
otherwise cause mutations by mispairing
or lead to breaks in DNA during
replication. BER is initiated by DNA
glycosylases, which recognize and
remove specific damaged or
inappropriate bases, forming AP sites.
These are then cleaved by an AP
endonuclease. The resulting single-strand
break can then be processed by either
short-patch (where a single nucleotide is
replaced) or long-patch BER (where 2–
Basic steps of base excision repair
10 new nucleotides are synthesized).[1]

Contents
Lesions processed by BER
The choice between long-patch
and short-patch repair
Proteins involved in base
excision repair
DNA glycosylases
AP endonucleases
End processing enzymes
DNA polymerases
Flap endonuclease
DNA ligase
Links with cancer
Epigenetic deficiencies in
cancers
MBD4
NEIL1
Links with cognition
Decline in BER with age
See also
References
External links

Lesions processed by BER

Single bases in DNA can be chemically damaged by a variety of
mechanisms, the most common ones being deamination, oxidation,
and alkylation. These modifications can affect the ability of the base
to hydrogen-bond, resulting in incorrect base-pairing, and, as a
consequence, mutations in the DNA. For example, incorporation of
adenine across from 8-oxoguanine (right) during DNA replication
causes a G:C base pair to be mutated to T:A. Other examples of base
8-oxoguanine forms a Hoogsteen
lesions repaired by BER include: base pair with adenine

Oxidized bases: 8-oxoguanine, 2,6-diamino-4-hydroxy-5-

formamidopyrimidine (FapyG, FapyA)
Alkylated bases: 3-methyladenine, 7-methylguanosine
Deaminated bases: hypoxanthine formed from deamination of adenine. Xanthine formed from
deamination of guanine. (Thymidine products following deamination of 5-methylcytosine are
more difficult to recognize, but can be repaired by mismatch-specific glycosylases)
Uracil inappropriately incorporated in DNA or formed by deamination of cytosine[2]

In addition to base lesions, the downstream steps of BER are also utilized to repair single-strand breaks.

The choice between long-patch and short-patch repair

The choice between short- and long-patch repair is currently under investigation. Various factors are thought to
influence this decision, including the type of lesion, the cell cycle stage, and whether the cell is terminally
differentiated or actively dividing.[3] Some lesions, such as oxidized or reduced AP sites, are resistant to pol β
lyase activity and, therefore, must be processed by long-patch BER.

Pathway preference may differ between organisms, as well. While human cells utilize both short- and long-
patch BER, the yeast Saccharomyces cerevisiae was long thought to lack a short-patch pathway because it
does not have homologs of several mammalian short-patch proteins, including pol β, DNA ligase III, XRCC1,
and the kinase domain of PNKP. The recent discovery that the poly-A polymerase Trf4 possesses 5' dRP lyase
activity has challenged this view.[4]

Proteins involved in base excision repair

DNA glycosylases

DNA glycosylases are responsible for initial recognition of the lesion. They flip the damaged base out of the
double helix, as pictured, and cleave the N-glycosidic bond of the damaged base, leaving an AP site. There are
two categories of glycosylases: monofunctional and bifunctional. Monofunctional glycosylases have only
glycosylase activity, whereas bifunctional glycosylases also possess AP lyase activity. Therefore, bifunctional
glycosylases can convert a base lesion into a single-
strand break without the need for an AP endonuclease. β-
Elimination of an AP site by a glycosylase-lyase yields a
3' α,β-unsaturated aldehyde adjacent to a 5' phosphate,
which differs from the AP endonuclease cleavage
product.[5] Some glycosylase-lyases can further perform
δ-elimination, which converts the 3' aldehyde to a 3'
phosphate. A wide variety of glycosylases have evolved
to recognize different damaged bases. Examples of DNA
glycosylases include Ogg1, which recognizes 8-
oxoguanine, Mag1, which recognizes 3-methyladenine,
and UNG, which removes uracil from DNA.
Uracil DNA glycosylase flips a uracil residue out of
AP endonucleases the duplex, shown in yellow.

The AP endonucleases cleave an AP site to yield a 3'

hydroxyl adjacent to a 5' deoxyribosephosphate (dRP). AP endonucleases are divided into two families based
on their homology to the ancestral bacterial AP endonucleaes endonuclease IV and exonuclease III.[6] Many
eukaryotes have members of both families, including the yeast Saccharomyces cerevisiae, in which Apn1 is
the EndoIV homolog and Apn2 is related to ExoIII. In humans, two AP endonucleases, APE1 and APE2,
have been identified.[7] It is a member of the ExoIII family.

End processing enzymes

In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5'
end. In humans, polynucleotide kinase-phosphatase (PNKP) promotes formation of these ends during BER.
This protein has a kinase domain, which phosphorylates 5' hydroxyl ends, and a phosphatase domain, which
removes phosphates from 3' ends. Together, these activities ready single-strand breaks with damaged termini
for ligation. The AP endonucleases also participate in 3' end processing. Besides opening AP sites, they
possess 3' phosphodiesterase activity and can remove a variety of 3' lesions including phosphates,
phosphoglycolates, and aldehydes. 3'-Processing must occur before DNA synthesis can initiate because DNA
polymerases require a 3' hydroxyl to extend from.

DNA polymerases

Pol β is the main human polymerase that catalyzes short-patch BER, with pol λ able to compensate in its
absence.[8] These polymerases are members of the Pol X family and typically insert only a single nucleotide.
In addition to polymerase activity, these enzymes have a lyase domain that removes the 5' dRP left behind by
AP endonuclease cleavage. During long-patch BER, DNA synthesis is thought to be mediated by pol δ and
pol ε along with the processivity factor PCNA, the same polymerases that carry out DNA replication. These
polymerases perform displacing synthesis, meaning that the downstream 5' DNA end is "displaced" to form a
flap (see diagram above). Pol β can also perform long-patch displacing synthesis and can, therefore, participate
in either BER pathway.[9] Long-patch synthesis typically inserts 2-10 new nucleotides.

Flap endonuclease
FEN1 removes the 5' flap generated during long patch BER. This endonuclease shows a strong preference for
a long 5' flap adjacent to a 1-nt 3' flap.[10] The yeast homolog of FEN1 is RAD27. In addition to its role in
long-patch BER, FEN1 cleaves flaps with a similar structure during Okazaki fragment processing, an
important step in lagging strand DNA replication.

DNA ligase

DNA ligase III along with its cofactor XRCC1 catalyzes the nick-sealing step in short-patch BER in
humans[11][12]. DNA ligase I ligates the break in long-patch BER.[13]

Links with cancer

Defects in a variety of DNA repair pathways lead to cancer predisposition, and BER appears to follow this
pattern. Deletion mutations in BER genes have shown to result in a higher mutation rate in a variety of
organisms, implying that loss of BER could contribute to the development of cancer. Indeed, somatic
mutations in Pol β have been found in 30% of human cancers, and some of these mutations lead to
transformation when expressed in mouse cells.[14] Mutations in the DNA glycosylase MYH are also known to
increase susceptibility to colon cancer.[15]

Epigenetic deficiencies in cancers

Epigenetic alterations (epimutations) in base excision repair genes have only recently begun to be evaluated in
a few cancers, compared to the numerous previous studies of epimutations in genes acting in other DNA repair
pathways (such as MLH1 in mismatch repair and MGMT in direct reversal). Some examples of epimutations
in base excision repair genes that occur in cancers are summarized below.

MBD4

MBD4 (methyl-CpG-binding domain protein 4) is a glycosylase

employed in an initial step of base excision repair. MBD4 protein
binds preferentially to fully methylated CpG sites and to the altered
DNA bases at those sites. These altered bases arise from the frequent
hydrolysis of cytosine to uracil (see image) and hydrolysis of 5-
methylcytosine to thymine, producing G:U and G:T base pairs.[16] If Hydrolysis of cytosine to uracil
the improper uracils or thymines in these base pairs are not removed
before DNA replication, they will cause transition mutations. MBD4
specifically catalyzes the removal of T and U paired with guanine (G) within CpG sites.[17] This is an
important repair function since about 1/3 of all intragenic single base pair mutations in human cancers occur in
CpG dinucleotides and are the result of G:C to A:T transitions.[17][18] These transitions comprise the most
frequent mutations in human cancer. For example, nearly 50% of somatic mutations of the tumor suppressor
gene p53 in colorectal cancer are G:C to A:T transitions within CpG sites.[17] Thus, a decrease in expression
of MBD4 could cause an increase in carcinogenic mutations.

MBD4 expression is reduced in almost all colorectal neoplasms due to methylation of the promoter region of
MBD4.[19] Also MBD4 is deficient due to mutation in about 4% of colorectal cancers.[20]

A majority of histologically normal fields surrounding neoplastic growths (adenomas and colon cancers) in the
colon also show reduced MBD4 mRNA expression (a field defect) compared to histologically normal tissue
from individuals who never had a colonic neoplasm.[19] This finding suggests that epigenetic silencing of
MBD4 is an early step in colorectal carcinogenesis.

In a Chinese population that was evaluated, the MBD4 Glu346Lys polymorphism was associated with about a
50% reduced risk of cervical cancer, suggesting that alterations in MBD4 may be important in cancer.[21]

NEIL1

NEIL1 recognizes (targets) and removes certain oxidatively-damaged bases and then incises the abasic site via
β,δ elimination, leaving 3′ and 5′ phosphate ends. NEIL1 recognizes oxidized pyrimidines,
formamidopyrimidines, thymine residues oxidized at the methyl group, and both stereoisomers of thymine
glycol.[22] The best substrates for human NEIL1 appear to be the hydantoin lesions, guanidinohydantoin, and
spiroiminodihydantoin that are further oxidation products of 8-oxoG. NEIL1 is also capable of removing
lesions from single-stranded DNA as well as from bubble and forked DNA structures. A deficiency in NEIL1
causes increased mutagenesis at the site of an 8-oxo-Gua:C pair, with most mutations being G:C to T:A
transversions.[23]

A study in 2004 found that 46% of primary gastric cancers had reduced expression of NEIL1 mRNA, though
the mechanism of reduction was not known.[24] This study also found that 4% of gastric cancers had
mutations in NEIL1. The authors suggested that low NEIL1 activity arising from reduced expression and/or
mutation in NEIL1 was often involved in gastric carcinogenesis.

A screen of 145 DNA repair genes for aberrant promoter methylation was performed on head and neck
squamous cell carcinoma (HNSCC) tissues from 20 patients and from head and neck mucosa samples from 5
non-cancer patients.[25] This screen showed that NEIL1, with substantially increased hypermethylation, had
the most significantly different frequency of methylation. Furthermore, the hypermethylation corresponded to a
decrease in NEIL1 mRNA expression. Further work with 135 tumor and 38 normal tissues also showed that
71% of HNSCC tissue samples had elevated NEIL1 promoter methylation.[25]

When 8 DNA repair genes were evaluated in non-small cell lung cancer (NSCLC) tumors, 42% were
hypermethylated in the NEIL1 promoter region.[26] This was the most frequent DNA repair abnormality
found among the 8 DNA repair genes tested. NEIL1 was also one of six DNA repair genes found to be
hypermethylated in their promoter regions in colorectal cancer.[27]

Links with cognition

Active DNA methylation and demethylation is required for the cognition process of memory formation and
maintenance.[29] In rats, contextual fear conditioning can trigger life-long memory for the event with a single
trial, and methylation changes appear to be correlated with triggering particularly long-lived memories.[29]
With contextual fear conditioning, after 24 hours, DNA isolated from the rat brain hippocampus region had
2097 differentially methylated genes, with a proportion being demethylated.[29] As reviewed by Bayraktar and
Kreutz,[28] DNA demethylation is dependent on base excision repair (see figure).

Physical exercise has well established beneficial effects on learning and memory (see Neurobiological effects
of physical exercise). BDNF is a particularly important regulator of learning and memory.[30] As reviewed by
Fernandes et al.,[31] in rats, exercise enhances the hippocampus expression of the gene Bdnf, which has an
essential role in memory formation. Enhanced expression of Bdnf occurs through demethylation of its CpG
island promoter at exon IV[31] and demethylation depends on base excision repair (see figure).[28]

Decline in BER with age

The activity of the DNA glycosylase that
removes methylated bases in human
leukocytes declines with age.[32] The
reduction in the excision of methylated
bases from DNA suggests an age-
dependent decline in 3-methyladenine
DNA glycosylase, a BER enzyme
responsible for removing alkylated
bases.[32]

Young rats (4- to 5 months old), but not

old rats (24- to 28 months old), have the
ability to induce DNA polymerase beta
and AP endonuclease in response to
oxidative damage.[33]

See also
DNA mismatch repair
DNA repair
Homologous recombination
Non-homologous end joining
Nucleotide excision repair
Host-cell reactivation assay

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External links
Base+Excision+Repair (https://meshb.nlm.nih.gov/record/ui?name=Base%20Excision%20Rep
air) at the US National Library of Medicine Medical Subject Headings (MeSH)

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