Molecular Mechanism of Mammalian DNA Excision Repair, DNA Damage Checkpoints and the Circadian Clock

哺乳动物 DNA 切除修复、DNA 损伤检查点和生物钟的分子机制

• 批准号: 9251831
• 负责人: AZIZ SANCAR
• 金额: $ 98.01万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2021-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9251831
• 关键词: Affect; Animals; Antineoplastic Agents; Area; Biochemistry; Biophysics; Cellular biology; Coupling; DNA; DNA Damage; DNA damage checkpoint; Disease; Excision Repair; Genetic; Goals; Health; Human; Human Genome; In Vitro; Lead; Link; Maps; Methods; Molecular; Nucleotide Excision Repair; Nucleotides; Physiology; Preclinical Drug Evaluation; Regulation; Research; Resolution; System; Validation; Work; base; cancer prevention; cancer therapy; carcinogenicity; circadian pacemaker; human DNA; improved; innovation; novel strategies; public health relevance; reconstitution

 DESCRIPTION (provided by applicant): We work on three inter-related subjects: mammalian DNA excision repair, DNA damage checkpoints, and the circadian clock. We have made a number of recent discoveries in all three areas that lead to deeper understanding of the interconnections between these three systems and are directly relevant to human health and disease treatment. We developed the XR-seq (excision Repair-sequencing) method to generate an excision repair map of the entire human genome at single nucleotide resolution; we have reconstituted an in vitro system that links nucleotide excision repair to the DNA damage checkpoint; and we have discovered regulation of excision repair by the circadian clock and developed novel approaches to understand the molecular mechanism of the mammalian circadian clock. We will apply these new conceptual and technical advances for the following objectives: (1) understand factors that affect excision repair of DNA damage by carcinogenic and by anticancer agents, (2) improve the in vitro system of excision repair-checkpoint coupling for potential use in anticancer drug screening and validation, and (3) characterize the molecular mechanism of the mammalian circadian clock and develop strategies of cancer prevention and cancer treatment based on clock control of human DNA excision repair activity. This approach is innovative because it combines biochemistry/biophysics, cell biology, genetics and animal physiology to understand the mechanistic basis and connections between mammalian DNA excision repair, DNA damage checkpoints, and of the circadian clock. The proposed research is significant because of its relevance to cancer prevention and treatment.

 描述（由适用提供）：我们处理三个相互关联的主题：哺乳动物DNA惊喜维修，DNA损伤检查点和昼夜节律时钟。我们在所有三个领域中都发现了许多最新发现，从而使人们对这三个系统之间的互连有了更深入的了解，并且与人类健康和疾病治疗直接相关。我们开发了XR-SEQ（切除修复 - 测序）方法，以在单个核苷酸分辨率下生成整个人类基因组的切除修复图；我们重组了一个体外系统，该系统将核苷酸惊喜修复与DNA损伤检查点联系起来。我们已经发现了昼夜节律时钟对惊喜修复的调节，并开发了新的方法来了解哺乳动物昼夜节律时钟的分子机制。我们将在以下目标上运用这些新的概念和技术进步：（1）了解影响致癌物质和抗癌药对DNA损害的惊喜修复的因素，（2）改善满意度修复的体外系统的体外检查系统，用于检查抗癌药物筛查和验证中的潜在使用，以及基于癌症的策略和癌症癌症的癌症机械性均可在抗癌药物筛选和验证中的癌症癌症的癌症调节性，（3） DNA满意度修复活性。这种方法具有创新性，因为它结合了生物化学/生物物理学，细胞生物学，遗传学和动物生理学，以了解哺乳动物DNA惊喜修复，DNA损伤检查点与昼夜节律时钟之间的机械基础和连接。拟议的研究很重要，因为它与癌症的预防和治疗相关。