DNA Repair

DNA gets damaged constantly. UV light, chemical mutagens, reactive oxygen species, and spontaneous hydrolysis all cause lesions. Without repair, mutations would accumulate rapidly. Several distinct repair pathways exist, each specialized for a different kind of damage.

Proofreading

Part of replication itself. Most DNA polymerases have a 3’ to 5’ exonuclease activity that reads back after placing a new nucleotide. If the new base is not correctly paired, the polymerase chops it off and tries again. This catches most errors during synthesis.

Mismatch Repair (MMR)

Fixes the rare errors that escape proofreading. The mismatch repair system scans freshly replicated DNA, recognizes mispaired bases, and replaces the incorrect nucleotide on the newly synthesized strand (not the template). How does it know which strand is new? In bacteria, the parental strand is methylated at certain sequences and the new strand is not yet methylated. In eukaryotes, the mechanism is less clear but probably uses nicks in the new strand.

MMR defects cause hereditary non-polyposis colorectal cancer (HNPCC, Lynch syndrome) - mutations in MLH1, MSH2, and other MMR genes.

Base Excision Repair (BER)

Repairs single damaged bases (like oxidized or deaminated ones). A DNA glycosylase removes the damaged base, leaving an abasic site. An endonuclease nicks the backbone. A polymerase fills the gap with a correct nucleotide, and ligase seals the nick.

Nucleotide Excision Repair (NER)

Repairs bulky lesions that distort the helix, like UV-induced thymine dimers. Endonucleases cut out a short segment (~12-24 nucleotides) around the damage. Polymerase fills the gap, ligase seals it.

NER defects cause xeroderma pigmentosum (XP) - patients cannot repair UV damage, develop skin cancers as children, and must avoid sunlight entirely.

Double-Strand Break Repair

Double-strand breaks are the worst kind of damage - both strands are cut. Two repair paths:

• Homologous recombination (HR): uses an identical sister chromatid as a template. Accurate but requires an intact copy, so it is restricted to the S and G2 phases of the cell cycle. BRCA1 and BRCA2 proteins are essential components. Mutations in BRCA$\frac{1}{2}$ cause hereditary breast and ovarian cancer.
• Non-homologous end joining (NHEJ): directly glues the two ends back together without a template. Fast but error-prone - small insertions or deletions often result. Used throughout the cell cycle.

Clinical Examples