Chemical Biology of DNA and RNA Alkylation

DNA 和 RNA 烷基化的化学生物学

• 批准号: 10597056
• 负责人: Yinsheng Wang
• 金额: $ 87.74万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-12 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10597056
• 关键词: Alkylating Agents; Alkylation; Area; Biology; Bypass; Cells; Chemicals; Chemistry; DNA; DNA Alkylation; DNA Damage; DNA Repair; DNA biosynthesis; DNA lesion; DNA-Directed DNA Polymerase; Disease; Environment; Environmental Exposure; Exposure to; Genetic Transcription; Genome Stability; Goals; Health; Human; Knowledge; Metabolic Activation; Metabolism; Molecular; Outcome; Post-Transcriptional RNA Processing; Prevention; Prevention approach; Proteins; Proteomics; RNA; RNA methylation; Research; Role; Signal Transduction; Toxic Environmental Substances; Trinucleotide Repeat Expansion; environmental chemical; epitranscriptomics; human disease; insight; molecular pathology; nervous system disorder; repaired; response

ABSTRACT Alkylating agents are ubiquitously present in the environment, and they can alkylate DNA and RNA directly or after metabolic activation. The focus of the present R35 application is placed on the chemistry and biology of DNA and RNA alkylation, with the overarching goal of understanding the molecular mechanisms through which alkylating agents and other environmental chemicals exert their adverse human health effects. In particular, we will examine the roles of translesion synthesis DNA polymerases in the transcriptional bypass of DNA lesions in cultured human cells, identify DNA damage recognition proteins for alkylated DNA lesions, and investigate their roles in DNA damage response signaling and repair. We will also assess the implications of RNA methylation in the molecular pathology of trinucleotide repeat expansion diseases. The proposed research is a culmination of our established expertise in the areas of DNA damage and repair, proteomics and epitranscriptomics. Completion of the proposed research will lead to an unprecedented level of understanding about the human health consequences of exposure to alkylating agents and other environmental toxicants, and will ultimately result in approaches for the prevention and mitigation of adverse human health consequences arising from environmental exposure.

抽象的 烷基化剂在环境中普遍存在，它们可以直接烷基化DNA和RNA 或代谢激活后。目前 R35 应用的重点是化学和生物学 DNA 和 RNA 烷基化，总体目标是了解其分子机制 烷化剂和其他环境化学品对人类健康产生不利影响。特别是，我们 将检查跨损伤合成 DNA 聚合酶在 DNA 损伤转录旁路中的作用 培养的人类细胞，鉴定烷基化 DNA 损伤的 DNA 损伤识别蛋白，并研究它们的 DNA 损伤反应信号传导和修复中的作用。我们还将评估 RNA 甲基化的影响 三核苷酸重复扩增疾病的分子病理学。拟议的研究是 我们在 DNA 损伤和修复、蛋白质组学和表观转录组学领域积累了丰富的专业知识。 完成拟议的研究将导致对人类的理解达到前所未有的水平 接触烷化剂和其他环境毒物对健康造成的后果，最终将 产生预防和减轻由以下原因引起的不良人类健康后果的方法： 环境暴露。