Role of MRK in DNA Damage Response

MRK 在 DNA 损伤反应中的作用

• 批准号: 6871592
• 负责人: ROSAMARIA RUGGIERI
• 金额: $ 26.95万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-28 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6871592
• 关键词: DNA damage; DNA repair; RNA interference; SDS polyacrylamide gel electrophoresis; biological signal transduction; cell cycle; cell growth regulation; cell proliferation; immunoprecipitation; ionizing radiation; mass spectrometry; molecular oncology; neoplasm /cancer radiation therapy; neoplastic cell; neoplastic process; phosphorylation; protein kinase; protein structure function; radiation resistance; radiation sensitivity; radiobiology; site directed mutagenesis; western blottings

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.

描述（由申请人提供）：通过诱导细胞周期停滞并允许损害修复的时间，对DNA损伤的细胞反应导致癌症的辐射抗性。该提案的长期目标是确定DNA损伤响应的信号传导成分，该响应可以针对降低癌细胞的辐射耐药性。控制细胞周期停滞的监视机制称为检查点，由控制DNA修复的复杂信号通路网络以及其他功能之间的细胞周期停滞。 ATM-CHK2/CHKL-CDC25A CASCADE是含BRCT-MOTIF的蛋白MCD1，NBSL和53BP1的下游，在伽马射线诱导的S和G2相的细胞周期停滞中起着重要作用。蛋白激酶MRK通过伽马辐射激活，并有助于S期和G2相细胞周期停滞。发现MRK通过直接磷酸化CHK2参与了γ-辐射诱导的CHK2激活。此外，RNA干扰的MRK敲低可将53BP1的定位降低到DNA损伤部位，并使癌细胞对γ-辐射的致命作用敏感。这项研究的目的是阐明MRK通过测试以下假设来促进DNA损伤诱导的细胞周期停滞的机制：MRK在CASCADE中下游运行MRK下游，NBSL，NBSL，53BP1和ATM在CHK2激活和CDC25A激活和CDC25A Degractation中响应响应，gamma-radiation，Gamma-radadiation。具体目的将通过以下方式测试这些假设：1）定义响应于伽马辐射的MRK途径中工作的要素； 2）通过结构功能研究定义MRK激活的分子机制。 MRK功能的分子分析将提高我们对DNA损伤后细胞周期检查点调节的理解，并可以鉴定出旨在降低肿瘤辐射抗性的抗肿瘤剂的新靶标。