Systematic characterization of the enzyme-substrate network in protein Lysine methylation

蛋白质赖氨酸甲基化中酶-底物网络的系统表征

• 批准号: RGPIN-2017-04652
• 负责人: Li, ShawnShunCheng
• 金额: $ 2.48万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2017
• 资助国家: 加拿大
• 起止时间: 2017-01-01 至 2018-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=629558
• 关键词: Systematic; characterization; enzyme; substrate; network

Despite the importance of Lys methylation in normal physiology and the pathogenesis of complex diseases such as cancer and neurological disorder, we know little about this post-translational modification (PTM) beyond its role on histone modification. We propose here to define the enzyme-substrate network of lysine methyltransferases (KMTs) and methyllyinse demethylases (KDMs) in order to understand the function of Lys methylation. As an important step towards this ambitious goal, we will focus on characterizing the KMTs and KDMs that modify H3K4 methylation, a histone mark that is associated with actively transcribed genes. The importance of H3K4 methylation is underscored, on the one hand, by the large number of KMTs (>12) and KDMs (>6) that are capable of modifying the mark, and, on the other, by the lethality or severe developmental defects in mice in which the corresponding genes are ablated.

尽管赖氨酸甲基化在正常生理和复杂疾病如癌症和神经系统疾病的发病机制中具有重要意义，但除了对组蛋白修饰的作用外，我们对这种翻译后修饰（PTM）知之甚少。我们在这里提出定义赖氨酸甲基转移酶（KMTs）和甲基化赖氨酸脱甲基酶（KDMs）的酶-底物网络，以了解赖氨酸甲基化的功能。作为实现这一雄心勃勃的目标的重要一步，我们将专注于表征修饰H3 K4甲基化的KMT和KDM，H3 K4甲基化是一种与活跃转录基因相关的组蛋白标记。一方面，H3 K4甲基化的重要性通过能够修饰标记的大量KMT（>12）和KDM（>6），以及另一方面，通过其中相应基因被消除的小鼠中的致死性或严重发育缺陷来强调。