Regulation and Function of SUMO-1 Protein Modification

描述(申请人提供)：SUMOS(小泛素相关修饰物)是大约100个氨基酸的蛋白质，它们在翻译后与数百种其他蛋白质共价连接，从而调节广泛的细胞过程。我们发现，与泛素化和磷酸化一样，苏莫化是哺乳动物细胞有丝分裂的重要调节因子。哺乳动物有三种相扑对偶：相扑-1、相扑-2和相扑-3(因为相扑-2和相扑-3有96%的相似之处，所以被称为相扑-2/3)。我们的发现表明，在有丝分裂过程中，SUMO-1和SUMO-2/3与独特的蛋白质亚群结合，并且它们调节不同的过程。然而，仍然存在许多悬而未决的问题。许多SUMO-1和SUMO-2/3修饰的相关靶点仍有待确定和表征，在有丝分裂过程中调节其时间修饰的机制尚不清楚。此外，相扑-1和相扑-2/3修饰对其靶标的特定分子效应，以及这些效应如何通过有丝分裂促进进展，仍然知之甚少。本次续期拨款申请中提出的研究目标是解决这些问题，并对苏莫化如何通过有丝分裂影响进展进行详细的分子理解。这些目标将通过四个具体目标来实现：(1)我们将确定SUMO-2/3修饰和结合在有丝分裂过程中对动粒相关蛋白的靶向和组装所起的作用。(2)我们将确定和表征在有丝分裂过程中调节蛋白质时间和空间总甲基化的分子机制。(3)我们将鉴定和鉴定后期和末期的染色体相关蛋白。(4)研究多聚体SUMO-2/3链和有丝分裂相关链结合蛋白的生物物理性质和功能。 公共卫生相关性：了解调节正常细胞分裂的因素和信号对于全面了解人类癌症的原因和开发新的抗癌疗法至关重要。我们已经确定SUMO(相扑蛋白与其他细胞蛋白的共价连接)是正常细胞分裂所必需的关键过程。我们的研究旨在提供一个更完整的了解如何在分子水平上苏莫化调节细胞分裂。从这些研究中获得的知识有可能导致开发检测和治疗人类癌症的新战略。

DESCRIPTION (provided by applicant): SUMOs (small ubiquitin-related modifiers) are ~100 amino acid proteins that are posttranslationally and covalently conjugated to hundreds of other proteins and thereby regulate a wide range of cellular processes. We have found that sumoylation, like ubiquitination and phosphorylation, is an essential regulator of mitosis in mammalian cells. Mammals express three SUMO paralogs: SUMO-1, SUMO-2 and SUMO-3 (because SUMO-2 and SUMO-3 are 96% identical, they are referred to as SUMO-2/3). Our findings indicate that SUMO-1 and SUMO-2/3 are conjugated to unique subsets of proteins during mitosis and that they regulate distinct processes. However, many unanswered questions still exist. Many of the relevant targets of SUMO-1 and SUMO-2/3 modification remain to be identified and characterized, and mechanisms regulating their temporal modification in mitosis are not known. In addition, the specific molecular effects of SUMO-1 and SUMO-2/3 modification on their targets, and how these effects facilitate progression through mitosis, are still poorly understood. The goals of the research proposed in this renewal grant application are to address these questions and develop a detailed molecular understanding of how sumoylation affects progression through mitosis. These goals will be achieved through four specific aims: (1) We will define the roles that SUMO-2/3 modification and binding play in the targeting and assembly of kinetochore-associated proteins during mitosis. (2) We will identify and characterize molecular mechanisms regulating the temporal and spatial sumoylation of proteins during mitosis. (3) We will identify and characterize chromosome-associated proteins sumoylated during anaphase and telophase. (4) We will investigate the biophysical properties and functions of polymeric SUMO-2/3 chains and mitosis-related chain-binding proteins. PUBLIC HEALTH RELEVANCE: Understanding the factors and signals that regulate normal cell division is essential for a full understanding of the causes of human cancer and for development of new anti-cancer therapies. We have identified sumoylation (the covalent linkage of the SUMO protein to other cellular proteins) as a critical process required for normal cell division. Our studies are designed to provide a more complete understanding of how sumoylation regulates cell division at the molecular level. Knowledge gained from these studies has the potential to lead to the development of new strategies for both the detection and for the treatment of human cancers.