Dependence on RAD52 and RAD1 for anticancer drug resistance mediated by inactivation of mismatch repair genes

Mismatch repair (MMR) proteins repair mispaired DNA bases and have an impor tant role in maintaining the integrity of the genome [1]. Loss of MMR has b een correlated with resistance to a variety of DNA damaging agents, includi ng many anticancer drugs [2]. How loss of MMR leads to resistance is not un derstood, but is proposed to be due to loss of futile MMR activity and/or r eplication stalling [3,4]. We report that inactivation of MMR genes (MLH1, MLH2, MSH2, MSH3, MSH6, but not PMS1) in isogenic strains of Saccharomyces cerevisiae led to increased resistance to the anticancer drugs cisplatin, c arboplatin and doxorubicin, but had no effect on sensitivity to ultraviolet C (UVC) radiation. Sensitivity to cisplatin and doxorubicin was increased in mlh1 mutant strains when the MLH1 gene was reintroduced, demonstrating a direct involvement of MMR proteins in sensitivity to these DNA-damaging ag ents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however , on drug sensitivities in the rad52 or rad1 mutant strains that are defect ive in mitotic recombination and removing unpaired DNA single strands. We p ropose a model whereby MMR proteins in addition to their role in DNA-damage recognition decrease adduct tolerance during DNA replication by modulating the levels of recombination-dependent bypass. This hypothesis is supported by the finding that, in human ovarian tumour cells, loss of hMLH1 correlat ed with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of h MLH1 expression.