Journal Article

Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines

Atul Mohindra, Laura E. Hays, Eric N. Phillips, Bradley D. Preston, Thomas Helleday and Mark Meuth

in Human Molecular Genetics

Volume 11, issue 18, pages 2189-2200
Published in print September 2002 | ISSN: 0964-6906
Published online September 2002 | e-ISSN: 1460-2083 | DOI: http://dx.doi.org/10.1093/hmg/11.18.2189
Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines

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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.

Journal Article.  7331 words.  Illustrated.

Subjects: Genetics and Genomics

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