DNA Repair

Dr. dr. Irsan Saleh, M.Biomed

Dept of Pharmacology and Pharmacy
Faculty of Medicine Universitas Sriwijaya
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Introduction
• DNA is continually subject to the threat of
damage by
▫ a wide variety of external agents
▫ spontaneous endogenous processes (Friedberg et al.,
1995).

• A given agent or process  complex variety of

DNA lesions, example
▫ ionizing radiation generates free radicals  single and
double strand breaks,
▫ destroy deoxyribose residues and
▫ induce numerous base alterations (Frimmer et al.,
1976).
Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

DNA damage can be classified in several

ways
• base modifications;
▫ chemical alterations,
▫ covalent joining between adjacent bases (the predominant
lesion is the UV-induced pyrimidine-pyrimidine dimer
▫ base loss.
These damages to DNA templates can result in misincorporation
during replication and can lead to heritable changes in DNA
sequence.
• intrastrand cross-linking, prevent DNA replication and
transcription.
• third type of DNA damage;
▫ DNA strand breaks, and more particularly, DNA double-
strand breaks (DSBs).
Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

DNA repair

• Involved in processes that:

▫ minimize cell killling,
▫ mutations,
▫ replication errors,
▫ persistence of DNA damage and
▫ genomic instability.
• Abnormalities in these processes have been
implicated in cancer and aging.
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

several different repair pathways in

mammalian cells
• single step reactions, a direct reversal by a single
enzyme like photolyase or O-6-methyl-DNA-
alkyltransferase,

• single and multi-step base excision mechanisms

(i.e., glycosylases) and

• multi-step reactions with pleiotropic specificities from

multiple protein components.
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

DNA repair
• There are 3 main ways DNA can be repaired:
▫ damage reversal,
▫ damage removal, and
▫ damage tolerance
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Damage reversal
• the simplest way to restore DNA
• the repair enzyme does not need to break the DNA
backbone to fix the errors.
• Photoreactivation is an example of damage reversal
because it involves breaking the bond that connects the
pyrimidine base dimers by using light
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Proof-reading
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Damage removal
• more complex than damage reversal, involves
replacing the damaged nucleotides with
functional nucleotides.

• There are 3 types of damage removal.

▫ base excision repair, a glycosylase enzyme cuts the
sugar-base bond, replaces the nucleotide, and reforms
the bond; an example is uracil glycosylase.
▫ mismatch repair, a DNA “spell-checking” enzyme
identifies bases that are mismatched and subsequently
replaces the wrongly paired base.
▫ nucleotide excision repair, endonucleases cut out a
segment of DNA that includes the error, and
polymerases are used to fill in the gap
Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Mismatch proofreading
Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

Damage tolerance
• used when a cell cannot fix the error and is forced to
tolerate the damage.

• Double strand break repair:

▫ Homologous recombination (HR)
Since DNA replicates via the semi-conservative theory, the strand
of DNA that does not contain the error will replicate normally
while the strand of DNA that contains the error will replicate and
form a mutant strand.
▫ Non homologous end joining (NHEJ)
The cell does try methods like recombinational repair and
mutagenic repair to fix the problem; however, these methods are
somewhat random and are not guaranteed to work properly
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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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Dr. dr. Muhammad Irsan Saleh, M.Biomed (FK Unsri)

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