Regulation and Function of SUMO Protein Modification

描述(申请人提供)：SUMOS是泛素相关的蛋白质，在翻译后与大量其他细胞蛋白质共价连接，从而调节各种基本功能。在从酵母到人类的各种生物中，相扑修饰调控着一系列过程，包括细胞周期的进展、DNA合成和修复、染色体分离、转录启动和核质运输。尽管在过去的5年里，在理解相扑是如何附着在底物上以及在识别相扑修饰调控的细胞过程方面已经取得了巨大的进展，但许多基本的问题仍然没有得到解答。对于特定的蛋白质如何识别和修饰以响应细胞生长或发育的变化，或者是什么特定的信号促进这一调控，人们知之甚少。此外，相扑修饰对底物的具体影响，以及这些影响如何转化为细胞功能的变化，目前还知之甚少。这项建议的目的是为了更全面地了解相扑修饰的细胞功能，并了解这些功能是如何在分子水平上调节和表现出来的。在这一更新应用中，建议的实验集中在：(1)定义有丝分裂过程中相扑-2/3修饰的功能(2)定义相扑-2/3修饰如何相对于相扑-1和细胞周期的不同阶段进行调节(3)确定相扑-1和相扑-2/3修饰如何影响蛋白质功能。重要的是，所有由相扑结合调节的细胞过程对于正常的细胞生长和分化都是必不可少的。因此，相扑结合途径的组成部分与多种人类疾病有关。相扑结合在处理淀粉样前体蛋白方面发挥了作用，淀粉样前体蛋白是阿尔茨海默病的核心，它通过修饰亨廷顿蛋白而导致亨廷顿病的病理。由于相扑在DNA修复和细胞周期控制中的作用，相扑结合途径也可能有助于多种人类癌症的发展。与相扑结合和I型糖尿病易感性的联系也有报道。了解相扑结合如何在分子水平上影响蛋白质功能，以及它如何调节细胞过程，对于确定它在人类疾病中的作用是至关重要的。

DESCRIPTION (provided by applicant): SUMOs are ubiquitin-related proteins that are posttranslationally and covalently conjugated to a large number of other cellular proteins, thereby regulating a variety of essential functions. In organisms ranging from yeast to man, SUMO modification regulates processes that include progression through the cell cycle, DNA synthesis and repair, chromosome segregation, initiation of transcription and nucleocytoplasmic transport. Although tremendous progress has been made over the past 5 years in understanding how SUMO is attached to substrates and in identifying cellular processes regulated by SUMO modification, many fundamental questions remain unanswered. Relatively little is known about how specific proteins are recognized and modified in response to the changes in cell growth or developement, or what specific signals facilitate this regulation. Also, the specific effects that SUMO modification has on substrates, and how these effects translate into changes in cell function, are poorly understood. The objectives of this proposal are to develop a more complete understanding of the cellular functions of SUMO modification and to understand how these functions are regulated and manifested at the molecular level. In this renewal application, the proposed experiments focus on: (1) defining the functions of SUMO-2/3 modification during mitosis (2) defining how SUMO-2/3 modification is regulated relative to SUMO-1 and to stages of the cell cycle (3) defining how SUMO-1 and SUMO-2/3 modification affects protein function. Importantly, all of the cellular processes regulated by SUMO conjugation are essential for normal cell growth and differentiation. Consequently, components of the SUMO conjugation pathway are associated with a variety of human diseases. SUMO conjugation plays a role in the processing of the amyloid precursor protein that is central to Alzheimer's disease, and it contributes to the pathology of Huntington's disease through modification of the Huntington protein. Due to functions in DNA repair and cell cycle control, the SUMO conjugation pathway may also contribute to the development of a variety of human cancers. Links to SUMO conjugation and susceptibility to type I diabetes have also been reported. Understanding how SUMO conjugation affects protein function at the moelcular level, and how it regulates cellular processes, is essential to defining how it roles in human diseases.