Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines.
Loss of mismatch repair (MMR) leads to a complex mutator phenotype that appears to drive the development of a subset of colon cancers. Here we show that MMR-deficient tumour cell lines are highly sensitive to the toxic effects of thymidine relative to MMR-proficient lines. This sensitivity was not a direct consequence of MMR deficiency or alterations of DNA precursor metabolism. Instead, MMR-defective tumour cell lines are also defective in homologous recombination repair (HRR) induced by DNA double-strand breaks. Furthermore, a frameshift mutation of the human RAD51 paralog XRCC2 found in the MMR-deficient uterine tumour cell line SKUT-1 can confer thymidine sensitivity when introduced into a MMR-proficient line. Like other cells with defective XRCC2, SKUT-1 is sensitive to mitomycin C, and MMR-proficient cells expressing the mutant XRCC2 allele become more sensitive to this agent. These data suggest that the thymidine sensitivity of MMR-deficient tumour cell lines may be a consequence of defects in the HRR pathway. The increased thymidine sensitivity and the loss of an important pathway for the repair of DNA double-strand breaks create new opportunities for therapies directed specifically against this subset of tumours.
Institute for Cancer Studies, University of Sheffield School of Medicine, Beech Hill Road, UK.
Atul
A
Mohindra
Laura E
LE
Hays
Eric N
EN
Phillips
Bradley D
BD
Preston
Thomas
T
Helleday
Mark
M
Meuth
D000595:Amino Acid Sequence; D020137:Base Pair Mismatch; D004260:DNA Repair / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D003854:Deoxyribonucleotides / Q000378:metabolism; D006801:Humans; D016685:Mitomycin / Q000494:pharmacology; D008969:Molecular Sequence Data; D009154:Mutation; D019384:Nucleic Acid Synthesis Inhibitors / Q000494:pharmacology; D011995:Recombination, Genetic; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism
D004268:DNA-Binding Proteins; D003854:Deoxyribonucleotides; D019384:Nucleic Acid Synthesis Inhibitors; C113187:XRCC2 protein, human; D016685:Mitomycin; D013936:Thymidine