Actions of DRM3 on DRM2 mediated DNA methylation

描述（由申请人提供）：该项目旨在对生物学中尚未解决的问题获得突破性的见解，该问题对了解心血管疾病的分子基础具有巨大的重要性：特定DNA序列如何靶向甲基化。在许多生物体中，DNA甲基化赋予基因表达的表观遗传控制。DNA甲基化的整体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甲基化具有深远的生物学意义，但特定的DNA序列最初是如何靶向甲基化的，在很大程度上仍然未知。我们建议通过研究DRM2的催化无活性同源物DRM3在将DRM2靶向染色质（Aim 1）和刺激DRM2甲基转移酶活性（Aim 2）中的作用来研究DRM2介导的DNA甲基化机制来解决这个问题。我还将通过遗传筛选确定有助于DRM3功能的新成分（目标3）。这些研究的完成将为识别特定DNA序列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，本项目的结果有望有助于加速研究DNA甲基化引起的肿瘤发生和心血管疾病的机制。

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.