Role of MRK in DNA Damage Response

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DESCRIPTION (provided by applicant): The cellular response to DNA damage contributes to radiation resistance in cancer by inducing cell cycle arrest and allowing time for damage repair. The long-term objective of this proposal is to identify signaling components of the DNA damage response that could be targeted to decrease radiation resistance in cancer cells. The surveillance mechanisms that control cell cycle arrest are called checkpoints and consist of a complex network of signaling pathways that control DNA repair as well as cell cycle arrest among other functions. The ATM-Chk2/Chkl-Cdc25A cascade, downstream of the BRCT-motif-containing proteins MCD1, Nbsl and 53BP1, plays an important role in gamma-radiation-induced cell cycle arrest in S and G2 phase. The protein kinase MRK is activated by gamma-radiation and contributes to S-phase and G2-phase cell cycle arrest. MRK was found to participate in the gamma-radiation-induced Chk2 activation by directly phosphorylating Chk2. In addition, MRK knockdown by RNA interference reduces 53BP1 localization to sites of DNA damage and sensitizes cancer cells to the lethal effects of gamma-radiation. The goal of this study is to elucidate the mechanism through which MRK contributes to DNA-damage-induced cell cycle arrest by testing the following hypothesis: MRK operates downstream ofMDC1, Nbsl, 53BP1 and ATM, in the cascade that leads to Chk2 activation and Cdc25A degradation in response to, gamma-radiation. The specific aims will test these hypotheses by: 1) Defining the elements that operate in the MRK pathway in response to gamma-radiation; and 2) Defining the molecular mechanism of MRK activation through structure-function studies. The molecular analysis of the function of MRK will improve our understanding of cell cycle checkpoint regulation following DNA damage and could identify novel targets for the development of antineoplastic agents aimed at decreasing tumor radiation resistance.