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: 9071163
• 负责人: AZIZ SANCAR
• 金额: $ 90.47万
• 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/9071163
• 关键词: Affect; Animal Genetics; Antineoplastic Agents; Area; Biochemistry; Biophysics; Cellular biology; Coupling; DNA; DNA Damage; DNA damage checkpoint; Disease; Excision Repair; 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; 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（由申请人提供）：我们致力于三个相互关联的主题：哺乳动物 DNA 切除修复、DNA 损伤检查点和生物钟。我们在这三个领域取得了许多最新发现，这些发现使我们对相互联系有了更深入的了解。我们开发了 XR-seq（切除修复测序）方法，以单核苷酸分辨率生成整个人类基因组的切除修复图谱；重建了一个将核苷酸切除修复与DNA损伤检查点联系起来的体外系统；我们发现了生物钟对切除修复的调节，并开发了新的方法来理解哺乳动物生物钟的分子机制，我们将应用这些新的概念和方法。实现以下目标的技术进步：(1) 了解影响致癌物和抗癌药物对 DNA 损伤切除修复的因素，(2) 改进切除修复-检查点耦合的体外系统，以潜在用于抗癌药物筛选和验证，以及（3）表征哺乳动物生物钟的分子机制，并基于人类DNA切除修复活性的时钟控制制定癌症预防和癌症治疗策略。这种方法是创新的，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 切除修复、DNA 损伤检查点和生物钟之间的机制基础和联系。这项研究因其与癌症预防和治疗的相关性而具有重要意义。