SUMO conjugation in cell biology and Development

描述（由申请人提供）：项目概述：SUMO是一种泛素样蛋白，与多种靶蛋白可逆缀合，从而作为控制蛋白质亚细胞定位和生化活性的灵活开关。SUMO结合（“SUMO化”）在许多重要的生物学过程中起着核心作用，包括表观遗传和模式形成。本研究的长期目标是使用易于操作的模式生物果蝇来阐明类泛素化与这些生物学现象之间的联系。具体目标是：1.确定SUMO在Polycomb Group（PcG）功能中的作用。PcG因子在维持调节发育的基因的沉默表观遗传状态中起着重要作用。两个PcG因子，Ph和Scm，似乎是SUMO化的调节靶点。遗传学、细胞生物学和生物化学方法将被用来在这些蛋白质的类小泛素化和转录沉默之间建立机械联系。2.对基因型和发育阶段对SUMO结合蛋白谱的影响进行系统分析。SUMO的多效性表明存在许多未鉴定的SUMO结合靶点。蛋白质组学技术将用于表征完整生物体中SUMO结合蛋白的谱，作为基因型和发育阶段的函数。SUMO结合蛋白质的多维数据库的创建将使我们能够测试关于SUMO结合和去结合酶如何确定结合的特异性的假设，以及关于SUMO在蛋白质生物发生、表观遗传转录控制和胚胎发生等过程中的作用的假设。相关性：sumoylation途径与神经退行性疾病和癌症都有关。例如，亨廷顿蛋白（亨廷顿病的致病蛋白）的类小泛素化加剧了该疾病的果蝇模型中的神经变性。此外，许多癌蛋白（c-jun，elk-1和TEL）和肿瘤抑制蛋白（p53，RB和PML）的类小泛素化调节其功能。因此，这里提出的研究将促进我们对人类疾病的理解。

DESCRIPTION (provided by applicant): Project Summary: SUMO is a ubiquitin-like protein that is reversibly conjugated to a wide variety of target proteins, thereby serving as a flexible switch to control protein subcellular localization and biochemical activity. SUMO conjugation ("sumoylation") plays central roles in many crucial biological processes including epigenetic inheritance and pattern formation. The long-term goal of this research is to illuminate the connections between sumoylation and these biological phenomena using the easily manipulated model organism Drosophila melanogaster. The specific aims are: 1. To determine the role of SUMO in Polycomb Group (PcG) function. PcG factors play essential roles in maintaining the silent epigenetic state of genes that regulate development. Two PcG factors, Ph and Scm, appear to be regulatory targets of sumoylation. Genetic, cell biological, and biochemical approaches will be employed to make mechanistic connections between the sumoylation of these proteins and transcriptional silencing. 2. To carry out a system wide analysis of the effects of genotype and developmental stage on the spectrum of SUMO-conjugated proteins. The pleiotropic roles of SUMO suggest the existence of many unidentified SUMO conjugation targets. Proteomic techniques will be used to characterize the spectrum of SUMO conjugated proteins in the intact organism as a function of genotype and developmental stage. The creation of a multi-dimensional database of SUMO-conjugated proteins will allow us to test hypotheses about how SUMO conjugating and deconjugating enzymes determine the specificity of conjugation, and about the role of SUMO in such processes as protein biogenesis, epigenetic transcriptional control, and embryogenesis. Relevance: The sumoylation pathway has been implicated in both neurodegenerative disorders and cancer. For example, sumoylation of Huntingtin, the pathogenic protein in Huntington's disease, exacerbates neurodegeneration in a Drosophila model of this disease. Furthermore, the sumoylation of numerous oncoproteins (c-jun, elk-1, and TEL) and tumor suppressor proteins (p53, RB, and PML) modulates their function. Consequently, the research proposed here will advance our understanding of human disease.