Mechanisms Regulating DNA Methylation Maintenance in Chromatin

项目概要/摘要 DNA甲基化和组蛋白翻译后修饰（PTM）对染色质模板化的 这些“表观遗传”标记在癌症中常常受到异常调节。阐明 因此，控制DNA甲基化和组蛋白PTM的机制对于改善我们的免疫功能非常重要。 了解表观遗传学在癌症中的作用。E3泛素连接酶UHRF 1与E3泛素连接酶基因连锁。 细胞DNA甲基化的维持和UHRF 1的失调与细胞增殖相关， 转移和对DNA损伤剂的超敏反应。UHRF 1最近与 DNA甲基化和癌症进展的调节表明这种蛋白可能是一种有利的治疗方法， 目标然而，UHRF 1生物学的许多基本方面尚不清楚。K99/R 00的首要目标是 因此，我们的建议是促进我们对UHRF 1与染色质相互作用的理解， DNA甲基化遗传的调控。我的初步研究表明， 通过UHRF 1串联Tudor结构域在赖氨酸9处的组蛋白H3是其DNA甲基化维持所必需的 功能本提案中的研究将以这些发现为基础：1）定义多价染色质如何 参与驱动UHRF的DNA甲基化维持功能1，2）决定空间和 UHRF 1对DNA甲基化维持的时间贡献，3）定义UHRF 1相互作用组，以及4） 开发化学探针作为研究UHRF 1功能的工具。这一建议得到了强有力的指导支持 和培训计划，建立一个成功的独立的研究生涯调查的坚实基础， 表观遗传程序的调节及其功能障碍如何导致癌症的发生和发展。

PROJECT SUMMARY/ABSTRACT DNA methylation and histone post-translational modifications (PTMs) elicit influence on chromatin-templated biological processes, and these `epigenetic' marks are often aberrantly regulated in cancers. Elucidation of mechanisms controlling DNA methylation and histone PTMs are therefore important to better our understanding of the role of epigenetics in cancer. The E3 ubiquitin ligase UHRF1 is genetically linked to the maintenance of cellular DNA methylation and deregulation of UHRF1 correlates with cell proliferation, metastasis, and hypersensitivity to DNA damaging agents. These recent connections of UHRF1 to the regulation of DNA methylation and cancer progression suggest this protein may be a favorable therapeutic target. Yet, many fundamental aspects of UHRF1 biology are not known. The overarching goal of this K99/R00 proposal is therefore to advance our understanding of the interaction of UHRF1 with chromatin and the regulation of DNA methylation inheritance. My preliminary studies established that recognition of methylated histone H3 at lysine 9 by the UHRF1 tandem Tudor domain is required for its DNA methylation maintenance function. Studies in this proposal will build upon these findings to: 1) define how multivalent chromatin engagement drives the DNA methylation maintenance function of UHRF1, 2) determine the spatial and temporal contribution of UHRF1 to DNA methylation maintenance, 3) define the UHRF1 interactome, and 4) develop chemical probes as tools to study UHRF1 function. This proposal is supported by a strong mentorship and training plan, building a solid foundation for a successful independent research career investigating the regulation of the epigenetic program and how its dysfunction leads to the initiation and progression of cancer.