Cellular Responses to DNA Damage

细胞对 DNA 损伤的反应

• 批准号: 7593640
• 负责人: Peggy Hsieh
• 金额: $ 41.07万
• 依托单位: NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7593640
• 关键词: Adjuvant Therapy; Alkylating Agents; Apoptotic; Cell Cycle Checkpoint; Cisplatin; Colorectal Cancer; Cytotoxic agent; DNA; DNA Alkylation; DNA Damage; Family; Fluorouracil; Goals; In Vitro; MLH1 gene; Mediating; Mismatch Repair; Molecular; Pathway interactions; Patients; Pharmaceutical Preparations; Phosphatidylinositols; Phosphorylation; Phosphotransferases; Population; Proteins; Recruitment Activity; Resistance; Signal Transduction; Site; System; Thioguanine; Thymidine; analog; base; cell killing; chemotherapy; cytotoxicity; member; response

We have developed an in vitro system whereby we can study the molecular mechanism underlying activation of the ATR kinase signaling cascade in response to DNA alkylation. ATR is a member of the phosphoinositide 3-kinase-related kinase (PIKK) family involved in DNA damage signaling. We have shown that MutSalpha and MutLalpha recruit ATR to sites of cytoxic O6-methylguanine-thymidine mispairs resulting in activation of the ATR kinase activity and phosphorylation of cell cycle checkpoint proteins such as Chk1 and SMC1. ATR-dependent cell killing mediate by p53-dependent pathways contributes to the cytotoxicity of DNA alkylating agents. Modified base analogs commonly used as adjuvant therapy for colorectal cancer such as fluorouracil are currently being examined to see if they also elicit MMR-dependent cell killing.

我们已经开发了一个体外系统，通过该系统我们可以研究ATR激酶信号级联在DNA烷基化反应中激活的分子机制。ATR是参与DNA损伤信号传导的磷酸肌苷3激酶相关激酶（PIKK）家族的一员。我们已经证明MutSalpha和mutla α将ATR招募到细胞毒性o6 -甲基鸟嘌呤-胸腺嘧啶错配位点，导致ATR激酶活性的激活和细胞周期检查点蛋白（如Chk1和SMC1）的磷酸化。由p53依赖途径介导的atr依赖性细胞杀伤有助于DNA烷基化剂的细胞毒性。通常用作结直肠癌辅助治疗的修饰碱基类似物，如氟尿嘧啶，目前正在进行研究，以确定它们是否也会引起mmr依赖性细胞杀伤。