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: 9895813
• 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 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9895813
• 关键词: Affect; Animals; Antineoplastic Agents; Area; Biochemistry; Biophysics; Cellular biology; Coupling; DNA; DNA Damage; DNA damage checkpoint; Disease; Drug Screening; Excision Repair; Genetic; Goals; Health; Human; Human Genome; In Vitro; Lead; Link; Maps; Methods; Molecular; Nucleotide Excision Repair; Nucleotides; Physiology; 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.