Regulation and Function of SUMO-1 Protein Modification

SUMO-1 蛋白修饰的调控和功能

• 批准号: 8243549
• 负责人: MICHAEL J. MATUNIS
• 金额: $ 34.42万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-03-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8243549
• 关键词: Address; Affect; Amino Acids; Anaphase; Applications Grants; Binding; Binding Proteins; Biochemical; CENP-E protein; Cell Cycle; Cell Proliferation; Cell division; Cell physiology; Cells; Chromatin; Chromosome Structures; Chromosomes; Detection; Development; Enzymes; Funding; Goals; Human; Kinetochores; Knowledge; Lead; Malignant Neoplasms; Mammalian Cell; Mammals; Mediating; Mitosis; Mitotic; Modification; Molecular; Normal Cell; Phosphorylation; Play; Post-Translational Protein Processing; Process; Property; Proteins; Regulation; Research; Research Design; Role; Signal Transduction; Small Ubiquitin-Related Modifier Proteins; Structure; Testing; Ubiquitin; Ubiquitination; cancer therapy; isopeptidase; paralogous gene; public health relevance; segregation; telophase

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.

描述（由申请人提供）：SUMO（小泛素相关修饰剂）是约 100 个氨基酸蛋白质，它们在翻译后与数百种其他蛋白质共价缀合，从而调节广泛的细胞过程。我们发现，苏酰化与泛素化和磷酸化一样，是哺乳动物细胞有丝分裂的重要调节因子。哺乳动物表达三种 SUMO 旁系同源物：SUMO-1、SUMO-2 和 SUMO-3（因为 SUMO-2 和 SUMO-3 96% 相同，因此被称为 SUMO-2/3）。我们的研究结果表明，SUMO-1 和 SUMO-2/3 在有丝分裂过程中与独特的蛋白质子集缀合，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。 SUMO-1 和 SUMO-2/3 修饰的许多相关靶点仍有待鉴定和表征，并且调节其在有丝分裂中的时间修饰的机制尚不清楚。此外，SUMO-1 和 SUMO-2/3 修饰对其靶点的具体分子效应，以及这些效应如何促进有丝分裂进展，仍然知之甚少。本次更新拨款申请中提出的研究目标是解决这些问题，并详细了解苏酰化如何影响有丝分裂的进展。这些目标将通过四个具体目标来实现：（1）我们将定义 SUMO-2/3 修饰和结合在有丝分裂过程中着丝粒相关蛋白的靶向和组装中所发挥的作用。 (2) 我们将鉴定和表征有丝分裂过程中调节蛋白质时空苏酰化的分子机制。 (3)我们将鉴定和表征在后期和末期期间SUMO化的染色体相关蛋白。 (4) 我们将研究聚合SUMO-2/3链和有丝分裂相关链结合蛋白的生物物理特性和功能。 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充分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 化（SUMO 蛋白与其他细胞蛋白的共价连接）是正常细胞分裂所需的关键过程。我们的研究旨在更全面地了解苏酰化如何在分子水平上调节细胞分裂。从这些研究中获得的知识有可能导致人类癌症检测和治疗的新策略的开发。