Human Molecular Genetics, 2002, Vol. 11, No. 18 2189-2200
© 2002 Oxford University Press
Defects in homologous recombination repair in mismatch-repair-deficient tumour cell lines
1Institute for Cancer Studies, University of Sheffield School of Medicine, Beech Hill Road, Sheffield S10 2RX, UK, 2Department of Oncological Sciences and 3Department of Biochemistry, University of Utah School of Medicine, Salt Lake City, UT 84112-5330, USA
Received May 20, 2002; Accepted June 28, 2002
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.
* To whom correspondence should be addressed. Tel: +44 1142713288; Fax: +44 1142713515; Email: m.meuth{at}sheffield.ac.uk
The author wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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