Chemical Biology of DNA and RNA Alkylation

摘要 烷基化试剂普遍存在于环境中，它们可以直接使dna和rna烷基化。 或在新陈代谢激活之后。本R35应用的重点放在化学和生物学上。 DNA和RNA烷基化，首要目标是了解通过什么分子机制 烷化剂和其他环境化学品对人类健康造成不利影响。特别是，我们 将研究跨损伤合成DNA聚合酶在DNA损伤转录旁路中的作用 培养的人类细胞，鉴定烷化DNA损伤的DNA损伤识别蛋白，并研究其 在DNA损伤反应信号和修复中的作用。我们还将评估RNA甲基化对 三核苷酸重复扩张性疾病的分子病理学。这项拟议的研究是一项 我们在DNA损伤和修复、蛋白质组学和表位转录组学领域的成熟专业知识。 这项拟议研究的完成将使人们对人类的了解达到前所未有的水平。 接触烷化剂和其他环境毒物的健康后果，并最终将 导致预防和减轻因下列原因而对人类健康造成的不利后果的办法 暴露在环境中。

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.