DNA repair genes and role in carcinogenesis

1. Concept

DNA repair genes correct errors arising during S-phase and from environmental damage. They are sometimes called “caretaker” genes: loss doesn’t directly drive growth but causes a mutator phenotype — mutations accumulate genome-wide → ↑ cancer risk. Loss of repair behaves like a tumor suppressor (two hits).

2. The three main systems

System	Repairs	Key genes	Defect → disease
Mismatch repair (MMR)	Base mispairs / replication slippage	MSH2+MSH6 (MutSα), MSH2+MSH3 (MutSβ), MLH1, PMS2	Microsatellite instability → Lynch syndrome (HNPCC) — colon, endometrial
Nucleotide excision repair (NER)	Bulky lesions / UV thymine dimers	XP genes, endonucleases	Xeroderma pigmentosum → UV skin cancers
Homologous recombination (HR)	Double-strand breaks (ionizing radiation)	BRCA1, BRCA2, ATM, RAD51	Breast/ovarian cancer; ataxia-telangiectasia (ATM)

• MMR — corrects mispaired bases (e.g. G-T); failure → microsatellite instability.
• NER — removes UV-induced pyrimidine dimers and resynthesizes the strand.
• HR — ATM senses DSB → phosphorylates BRCA1 → BRCA1–BRCA2–RAD51 complex repairs it.

3. Link to the damage-response checkpoint

• p53 integrates the response: arrests the cycle (p21) to allow repair, or triggers apoptosis if damage is irreparable.
• Failure of repair + failure of p53 → damaged DNA is replicated → accumulating mutations → carcinogenesis.

💡 High-yield: Repair (caretaker) gene loss = mutator phenotype. MMR → MSI → Lynch (HNPCC); NER → xeroderma pigmentosum (UV skin cancer); HR (BRCA1/2, ATM) → breast/ovarian, ataxia-telangiectasia. p53 governs the damage checkpoint (arrest vs apoptosis).