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MSH2-deficient Human Cells Exhibit a Defect in the Accurate Termination of Homology-directed Repair of DNA Double-Strand Breaks¹

Department of Biochemistry, Université de Montréal, Succ. Centre-Ville, Montréal, Québec, Canada H3C 3J7 [J-F. V.], and Department of Biochemistry [C. A.], Molecular Biology Program [I. C.], and Department of Microbiology and Immunology [A. B.], Université de Montréal, Centre de Recherche du CHUM, Hôpital Notre-Dame, Institut du Cancer de Montréal, Montréal, Québec, Canada H2L 4M1

Mutations in the mismatch repair (MMR) genes hMSH2 and hMLH1 have been associated with hereditary nonpolyposis colorectal cancer. Tumor cell lines that are deficient in MMR exhibit a high mutation rate, a defect in the response to certain types of DNA damage and in transcription-coupled repair, as well as an increase in the rate of gene amplification. We show here that hMSH2-deficient tumor cell lines lost most of their ability to accurately repair plasmid DNA double-strand breaks (DSBs) by homologous recombination, compared with MMR-proficient or hMLH1-deficient tumor cell lines. In all of these cell lines, DSB repair occurred almost exclusively by nonreciprocal homologous recombination: gene conversion (GC). However, there were two types of GC products: precise and rearranged. The rearranged products contained deletions or insertions of sequences and represented GC intermediates trapped at various stages and shunted to nonhomologous end joining. In MMR-proficient or MLH1-deficient cells, >50% of GC products were of the precise type, whereas in two MSH2-deficient backgrounds, this proportion decreased to 8%, whereas that of rearranged GC products increased by 2-fold. These results seem to predict a novel way by which MSH2-deficiency could promote mutation: deletion or insertion mutations associated with DSB repair, which may also contribute to cancer predisposition.

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