Regulation and Function of SUMO Protein Modification

描述（由申请人提供）：SUMO是泛素相关蛋白质，其与大量其他细胞蛋白质后结合和共价结合，从而调节多种基本功能。在从酵母到人类的生物体中，SUMO修饰调节包括细胞周期进展、DNA合成和修复、染色体分离、转录起始和核质转运的过程。尽管在过去的5年里，在理解SUMO如何附着于底物和识别由SUMO修饰调控的细胞过程方面取得了巨大进展，但许多基本问题仍然没有答案。对于特定蛋白质如何响应细胞生长或发育的变化而被识别和修饰，或者什么特定信号促进这种调节，我们知之甚少。此外，SUMO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。本提案的目的是更全面地了解SUMO修饰的细胞功能，并了解这些功能如何在分子水平上进行调节和表现。在该更新申请中，拟议的实验集中于：（1）定义有丝分裂期间SUMO-2/3修饰的功能（2）定义SUMO-2/3修饰相对于SUMO-1和细胞周期阶段如何调节（3）定义SUMO-1和SUMO-2/3修饰如何影响蛋白质功能。重要的是，SUMO结合调控的所有细胞过程对于正常细胞生长和分化都是必不可少的。因此，SUMO结合途径的组分与多种人类疾病相关。SUMO缀合在淀粉样前体蛋白的加工中起作用，淀粉样前体蛋白是阿尔茨海默病的核心，并且它通过修饰亨廷顿蛋白而促成亨廷顿病的病理学。由于在DNA修复和细胞周期控制中的功能，SUMO缀合途径也可能有助于多种人类癌症的发展。SUMO结合与I型糖尿病易感性的联系也有报道。了解SUMO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至关重要。

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.