Actions of DRM3 on DRM2 mediated DNA methylation

描述（由申请人提供）：该项目旨在获得对生物学中一个尚未解决的问题的突破性见解，该问题对了解心血管疾病的分子基础具有重要意义：特定DNA序列如何靶向甲基化。DNA甲基化赋予许多生物体中基因表达的表观遗传控制。DNA甲基化的全局改变现在被广泛认为是人类癌症和心血管疾病的一个促成因素。尽管DNA甲基化具有深刻的生物学重要性，但特定DNA序列最初如何被甲基化靶向仍然在很大程度上未知。我们建议通过研究DRM2介导的DNA甲基化的机制来解决这个问题，通过研究DRM3（DRM2的催化失活同源物）在将DRM2靶向染色质（Aim 1）和刺激DRM2甲基转移酶催化活性（Aim 2）中的作用。我还将通过基因筛选来识别有助于DRM3功能的新组件（Aim 3）。这些研究的完成将为识别特定DNA序列以启动甲基化的分子因子和相互作用提供重要的新信息。由于DNA甲基化在植物和动物中高度保守，该项目的结果有望有助于加速研究，以了解DNA甲基化引起的肿瘤发生和心血管疾病的机制。 公共卫生相关性：人类基因组不仅包含了构成人体的基本遗传信息，而且还包含了“自私的DNA”，它们的功能只是复制自己，而它们不受控制的复制会导致癌症。人体有一个防御系统来识别这些DNA，然后在这些DNA上添加一种特殊的化学标记，称为甲基化，以阻止它们的复制。该项目旨在了解特定DNA序列如何被识别和靶向甲基化的分子基础。

DESCRIPTION (provided by applicant): This project seeks to gain groundbreaking insights into an unresolved problem in biology that has vast importance to understand the molecular basis of cardiovascular disease: how specific DNA sequences are targeted for methylation. DNA methylation confers epigenetic control of gene expression in many organisms. Global alterations of DNA methylation are now widely recognized as a contributing factor in human cancer and cardiovascular. Despite the profound biological importance of DNA methylation, how particular DNA sequences are initially targeted for methylation remains largely unknown. We propose to address this question by investigating the mechanism of DRM2-mediated DNA methylation through the investigation of the role of DRM3, a catalytically inactive homology of DRM2, in targeting DRM2 to chromatin (Aim 1) and stimulating DRM2 methyltransferase catalytic activity (Aim 2). I will also identify new components that assist in DRM3 function by genetic screen (Aim 3). Completion of these studies will provide important new information about the molecular factors and interactions that recognize specific DNA sequences to initiate methylation. Because DNA methylation is highly conserved among plants and animals, results from this project are expected to help accelerate studies to understand the mechanisms of tumorigenesis and cardiovascular diseases caused by DNA methylation. PUBLIC HEALTH RELEVANCE: The human genome not only contains the basic genetic information for making a human body, but also contains "selfish DNAs" that function only to replicate themselves and their uncontrolled replication can cause cancers. The human body has a defense system to recognize and then add a special chemical mark, called methylation, on these DNAs to stop their replication. This project seeks to understand the molecular basis of how specific DNA sequences are recognized and targeted for methylation.