Defective homologous recombination repair and carcinogenesis

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A defect in homologous recombination repair has been implicated in carcinogenesis because hereditary breast cancer genes BRCA were shown to play an important role in homologous recombination repair. We have investigated a molecular mechanism of homologous recombination repair in human cells. Rad54B, a gene identified as a novel recombination repair gene, exhibits the double-strand DNA-dependent ATPase activity and is required for gene targeting in human cells. XRCC3, a member of Rad51 paralog, is required for homologous recombination via sister chromatids. Additionally, XRCC3 prevents DNA rereplication and endoreduplication, thereby ensuring chromosome integrity. The T241M variant, a genetic polymorphism implicated in cancer risk, exhibits intact recombination repair, but fails to prevent endoreduplication, suggesting that an increase in endoreduplication is associated with cancer risk. A similar phenotype is observed in a resolvase gene Mus81-deficient cells. This aberration is caused by Cyclin B/Cdc2 inhibition by Chk2 activation in response to DNA damage. Thus, the recombination machinery is tightly associated with DNA replication and cell-cycle regulation. This finding suggests that a defect in the DNA metabolic network induces chromosome instability.