Structure and Function of SET Domain Methyltransferases

组蛋白是组织和紧凑核染色质的主要支架蛋白。这些 蛋白质经历了多种类型的化学修饰，这些修饰控制着细胞内的各种过程 原子核。氨基酸赖氨酸的甲基化发生在几个组蛋白中，并与 基因表达的调控以及DNA修复过程和细胞分裂。组蛋白赖氨酸 甲基转移酶(HKMT)是催化组蛋白中特定赖氨酸甲基化的酶。 研究表明，HKMT对基因表达既有积极的调节作用，也有消极的调节作用， 取决于它们在组蛋白中甲基化的特定赖氨酸。最近，一些HKMTs被展示出来 使转录因子(激活基因表达的DNA结合蛋白)甲基化，这表明 这些酶在控制转录方面的作用比之前认为的更广泛。重要的是 这些酶与基因表达之间的直接关系凸显了HKMT在基因表达调控中的作用。 多种形式的癌症。几个HKMT的缺失、突变或过度表达已联系在一起 恶性肿瘤，如白血病和前列腺癌、乳腺癌、肺癌、结直肠癌和肝癌。为了获得 洞察HKMT在转录调控中的功能以及这些酶的破坏如何 会导致癌症，我们提出了几个实验来表征它们的蛋白质底物特异性和 阐明它们使核蛋白中特定赖氨酸残基甲基化的化学机制。 为了实现这些目标，我们将结合使用生物化学和结构生物学，其中我们将 确定与其蛋白质底物结合的这些酶的分子结构。总而言之，这是 研究不仅将提供对香港旅游管理公司核心职能的新见解，而且还将提供 在癌症治疗中开发针对这些酶的特定抑制剂的途径。 目的：从生化和结构两方面确定HKMT赖氨酸甲基化的化学机制 一种被称为Rubisco大亚基甲基转移酶(LSMT)的植物HKMT同源基因的研究。 目的：确定组蛋白和转录因子Set7/9的底物特异性 甲基转移酶，通过结构和生化技术。 目的：确定人类SET的结构和底物特异性，这是一种在调节中起关键作用的HKMT 细胞分裂过程中的基因沉默和适当的染色体分离。

Histones are the major scaffolding proteins which organize and compact nuclear DMAin chromatin. These proteins undergo numerous types of chemical modifications that govern a variety of processes in the nucleus. Methylation of the amino acid lysine occurs in several histones and has been linked to the regulation of gene expression as well as in DNA repair processes and cell division. Histone lysine methyltransferases (HKMTs) are enzymes that catalyze the methylation of specific lysines within histones. HKMTs have been shown to function as both positive and negative regulators of gene expression, depending on the specific lysine that they methylate in histones. Recently, some HKMTs have been shown to methylate transcription factors (DNA binding proteins that activate gene expression), suggesting that these enzymes have broader roles in controlling transcription than previously believed. The importance of HKMTs in regulating gene expression is underscored by direct relationships between these enzymes and numerous forms of cancer. Deletions, mutations, or over-expression of several HKMTs have been linked malignancies such as leukemias and prostate, breast, lung, colorectal, and hepatic cancers. In order to gain insight into the functions of HKMTs in transcriptional regulation and how disruption of these enzymes can lead to cancer, we propose several experiments to characterize their protein substrate specificities and elucidate the chemical mechanism through which they methylate specific lysine residues in nuclear proteins. To achieve these goals, we will use a combination of biochemistry and structural biology in which we will determine the molecular structures of these enzymes bound to their protein substrates. Taken together, this research will provide not only novel insights into the functions of HKMTs in the nucleus, but will also provide avenues for the development of specific inhibitors against these enzymes in the treatment of cancer. Aim1: Determine the chemical mechanism of lysine methylation of HKMTs via biochemical and structural studies of a plant HKMT homolog known as Rubisco large subunit methyltransferase (LSMT). Aim2: Determine the substrate specificity of human SET7/9, a histone and transcription factor methyltransferase, through structural and biochemical techniques. Aim3: Determine the structure and substrate specificity of human SETS, an HKMT that is pivotal in regulating gene silencing and proper chromosome separation during cell division.