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Molecular Biology and Genetics |
Department of Radiation Oncology [T. Y., J. E. S., H. H., M. W. W., S. E. B., S. S., M. L. V., W. D. S., T. J. K.] and Laboratory of Molecular Stress Responses [D. A. B.], Ireland Comprehensive Cancer Center, University Hospitals of Cleveland and Case Western Reserve University School of Medicine, Cleveland, Ohio 44106-4942
Our previous data demonstrated that cells deficient in MutL homologue-1 (MLH1) expression had a reduced and shorter G2 arrest after high-dose-rate ionizing radiation (IR), suggesting that the mismatch re pair (MMR) system mediates this cell cycle checkpoint. We confirmed this observation using two additional isogenetically matched human MLH1 (hMLH1)-deficient and -proficient human tumor cell systems: human ovarian cancer cells, A2780/CP70, with or without ectopically expressed hMLH1, and human colorectal carcinoma cells, RKO, with or without azacytidine treatment to reexpress hMLH1. We also examined matched MutS homologue-2 (hMSH2)-deficient and -proficient human endometrial carcinoma HEC59 cell lines to determine whether hMSH2, and MMR in general, is involved in IR-related G2 arrest responses. As in MLH1-deficient cells, cells lacking hMSH2 demonstrated a similarly altered G2 arrest in response to IR (6 Gy). These differences in IR-induced G2 arrest between MMR-proficient and -deficient cells were found regardless of whether synchronized cells were irradiated in G0/G1 or S phase, indicating that MMR indeed dramatically affects the G2-M checkpoint arrest. However, unlike the MMR-dependent damage tolerance response to 6-thioguanine exposures, no significant difference in the clonogenic survival of MMR-deficient cells compared with MMR-proficient cells was noted after high-dose-rate IR. In an attempt to define the signal transduction mechanisms responsible for MMR-mediated G2 arrest, we examined the levels of tyrosine 15 phosphorylation of cdc2 (phospho-Tyr15-cdc2), a key regulator of the G2-M transition. Increased phospho-Tyr15-cdc2 levels were observed in both MMR-proficient and -deficient cell lines after IR. However, the levels of the phospho-Tyr15-cdc2 rapidly decreased in MMR (hMLH1 or hMSH2)-deficient cell lines at times coincident with progress from the IR-induced G2 arrest through M phase. Thus, differences in the levels of phospho-Tyr15-cdc2 after high-dose-rate IR correspond temporally with the observed differences in the IR-induced G2 arrest, suggesting that MMR proteins may exert their effect on IR-induced G2 arrest by signaling the cdc2 pathway. Although MMR status does not significantly affect the survival of cells after high-dose-rate IR, it seems to regulate the G2-M checkpoint and might affect overall mutation rates.
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