Chemical Biology of DNA and RNA Alkylation

摘要 烷化剂广泛存在于环境中，它们可以直接将DNA和RNA烷化剂化 或在代谢活化之后。本发明R35应用的重点在于以下物质的化学和生物学： DNA和RNA烷基化，其总体目标是了解分子机制， 烷基化剂和其它环境化学品对人类健康产生不利影响。我们尤其 将研究跨损伤合成DNA聚合酶在转录旁路的DNA损伤中的作用， 培养的人类细胞，鉴定烷基化DNA损伤的DNA损伤识别蛋白，并研究其 在DNA损伤反应信号传导和修复中的作用。我们还将评估RNA甲基化在 三核苷酸重复序列扩增疾病的分子病理学。拟议中的研究是 我们在DNA损伤和修复、蛋白质组学和表观转录组学领域的专业知识。 完成拟议的研究将导致对人类的前所未有的了解 暴露于烷化剂和其他环境毒物的健康后果，并最终将 产生预防和减轻由下列因素引起的对人类健康的不利后果的办法： 环境暴露。

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.