DNA Repair and Cancer

Genome Instability Science, 26 July 2002, p. 544

Hoeijmakers, Nature 01

Damage tolerance Hoeijmakers, Nature 01 Translesion synthesis

SyndromeCancer Risk Defective repair process Xeroderma pigmentosum SkinNER, damage bypass* Hereditary non- polyposis colorectal cancer Colorectal cancerMMR, BER* BRCA1/BRCA2Breast/Ovarian cancerHomologous recombination (HR) Fanconi AnemiaLeukemia, othersCrosslink repair CockayneNoneTranscription coupled TrichothiodystrophyNoneTranscription coupled Ataxia telangiectasiaLymphomasDouble strand break Nijmegan breakageLymphomasDouble strand break WernerVarious, agingNot definitive BloomLeukemia, lymphomaLikely HR Genome instability syndromes

Major DNA repair pathways: Nucleotide excision repair (NER)-- deals with broad class of helix –distorting lesions that disrupt transcription and replication Base excision repair (BER)-- deals with small chemical alterations of bases. Particularly relevant for preventing mutation. Double-strand break (DSB) repair—Homologous recombination (HR) and Nonhomologous end-joining (NHEJ)

Mismatch repair (MMR)– corrects replication errors, and can repair alkylated bases.

NER Global genome Transcription- Coupled Repair (TCR) Xeroderma Pigmentosum (XP) Cockayne Syndrome Trichothiodystrophy

Xeroderma Pigmentosum Clinical symptoms: –Early onset severe photosensitivity to UV exposure –Highly elevated risk of skin cancer (median age of onset is 8, compared to almost 60 for the rest of us) –Ocular abnormalities –Varying severity of neurological abnormalities in some but not all patients Clinical subtypes –Complementation groups A through G, and XP-V

Xeroderma Pigmentosum Cellular and Biochemical phenotypes: –Chromosomal abnormalities –Sensitivity to killing by DNA damaging agents –Defective nucleotide excision repair (NER) (seen in most but not all patients) Patients are assigned to ‘complementation groups’ based on cellular tests and genetic screens

XP-variant

BER Association of cancer with alterations in pol beta Also – defects in MUTYH predispose to colon cancer, G T transversions

Hoeijmakers, Nature 01 DSB Repair HR- accurate, Primarily S/G2 NHEJ- error- prone Primarily G1 Ataxia telangiectasia ATM Nijmegan breakage syndrome NBS1 Breast cancer BRCA1 BRCA2 RAD51 Bloom syndrome BLM Werner syndrome WRN Fanconi anemia

BRCA1 and BRCA2 Breast cancer susceptibility genes Localize to sites of damage (damage foci) Both phosphorylated in response to damage Defects associated with breast and ovarian cancer Venkitanaram, Cell 2002, 108, p. 171 two RAD51 sites also on C-terminus

a b c e d f gene conversion crossover Fig. 1. HR repair of a DSB. See text at right for details. BLM regulates HJ resolution

Mismatch Repair Hoeijmakers, Nature 01

Colorectal Cancer ~ 150K cases and 56K deaths every year from CRC 90% of all cases are diagnosed in people 50 and older Tell family and friends to get a colonoscopy at 50!!!! Remaining 10% of cases (early onset) are mostly associated with one of two genetic syndromes: –Familial adenomatous polyposis (FAP) –Hereditary non-polyposis colorectal cancer (HNPCC)

HNPCC –caused by defects in MMR Estimated to cause 1 to 5% of all CRC cases –(not just CRC; stomach, ovary, endometrial, others ) Criteria –At least 3 relatives in 2 generations diagnosed, at least one diagnosed before the age of 50 –FAP excluded Lifetime risk of developing CRC is ~80% for patients –~30% risk for endometrial, ~10 for ovarian and gastric

HNPCC HNPCC tumors display a high frequency of DNA microsatellite instability (“MSI” or “MIN” vs “CIN”) –Many mono, di, and trinucleotide repeats in genome –HNPCC tumor DNA has a much higher number of changes in these simple repeated sequences Mismatch repair corrects errors caused by DNA polymerase ‘slippage’ events at repeat sequences

HNPCC Mutations in MSH2 and MLH1 genes account for >95% of all HNPCC cases “MSH” = MutS homolog “MLH” = MutL homolog Mutations in other MMR genes are much rarer, but have also been associated with HNPCC