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 important role in maintaining the integrity of the genome [1]. Loss of MMR has been correlated with resistance to a variety of DNA-damaging agents, including many anticancer drugs [2]. How loss of MMR leads to resistance is not understood, but is proposed to be due to loss of futile MMR activity and/or replication 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, carboplatin 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 agents. Inactivation of MLH1, MLH2 or MSH2 had no significant effect, however, on drug sensitivities in the rad52 or rad1 mutant strains that are defective in mitotic recombination and removing unpaired DNA single strands. We propose 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 correlated with acquisition of cisplatin resistance and increased cisplatin-induced sister chromatid exchange, both of which were reversed by restoration of hMLH1 expression.
Durant
S T
ST
CRC Department of Medical Oncology, CRC Beatson Laboratories, Glasgow, G61 1BD, UK.
Morris
M M
MM
Illand
M
M
McKay
H J
HJ
McCormick
C
C
Hirst
G L
GL
Borts
R H
RH
Brown
R
R
D000970:Antineoplastic Agents / Q000494:pharmacology; D020137:Base Pair Mismatch; D016190:Carboplatin / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D004260:DNA Repair; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins / Q000502:physiology*; D004317:Doxorubicin / Q000494:pharmacology; D004352:Drug Resistance, Microbial; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004720:Endonucleases / Q000502:physiology*; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D051721:Rad52 DNA Repair and Recombination Protein; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D029701:Saccharomyces cerevisiae Proteins; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014466:Ultraviolet Rays
D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D009363:Neoplasm Proteins; C497197:RAD52 protein, S cerevisiae; D051721:Rad52 DNA Repair and Recombination Protein; D029701:Saccharomyces cerevisiae Proteins; D004317:Doxorubicin; D016190:Carboplatin; D004720:Endonucleases; C069266:RAD1 protein, S cerevisiae; D045643:DNA Repair Enzymes; D002945:Cisplatin