REGULATION AND FUNCTION OF SUMO-1 PROTEIN MODIFICATION

SUMO-1是一种由101个氨基酸组成的多肽，与泛素有18%的序列同源性。和泛素一样，SUMO-1在转录后与大量的细胞内蛋白结合。然而，SUMO-1结合似乎是调节靶向底物的功能和/或定位，而不是它们的蛋白分解。无论是直接还是间接地，相扑-1结合都被认为是一种广泛的重要细胞功能的调节因子。被确定为SUMO-1结合底物的蛋白质包括RanGAP1(核质运输的调节器)、PML和Sp100(与癌症和神经退行性疾病相关的核内结构的成分)，以及IkappaBalpha(控制免疫和炎症反应的信号通路的调节器)。相扑-1结合也被认为是细胞周期和DNA修复的调节因子。尽管有初步迹象表明，相扑-1结合调节了一系列细胞功能，但相扑-1结合对单个蛋白质，从而对细胞过程的确切影响仍不清楚。该提案中概述的具体目标旨在提供对相扑-1结合、其对蛋白质功能的特定影响以及对细胞过程的更多全球影响的更详细的了解。这些目标将通过分析调节相扑-1结合和去结合的因素和信号，鉴定新的相扑-1底物，以及鉴定相扑-1相关蛋白SUMO-2来实现。相扑-1结合受E3样蛋白连接酶和去结合酶调节的假说将被调查。此外，通过对一种新的SUMO-1/SUMO-2底物BLM的分析，以及对粗线期精母细胞XY小体相关底物的分析，将研究SUMO-1接合与PML核体之间的功能关系。还将研究XY小体和PML核小体在功能上相关并共享共同的相扑-1偶联物的假设。

SUMO-1 is a 101 amino acid polypeptide that shares 18 percent sequence identity with ubiquitin. Like ubiquitin, SUMO-1 is posttransationally conjugated to a significant number of intracellular proteins. However, SUMO-1 conjugation appears to regulate the function and/or localization of targeted substrates, rather than their proteolysis. SUMO-1 conjugation has been implicated, either directly or indirectly, as a regulator of a wide range of important cell functions. Proteins identified as substrates for SUMO-1 conjugation include RanGAP1 (a regulator of nucleocytoplasmic transport), PML and Sp100 (components of intranuclear structures linked to cancer and neurodegenerative disease), and IkappaBalpha (a regulator of signaling pathways that control immune and inflammatory responses). SUMO-1 conjugation has also been implicated as a regulator of the cell cycle and DNA repair. In spite of the preliminary indications that SUMO-1 conjugation regulates a host of cell functions, the precise effects that SUMO-1 conjugation has on individual proteins, and consequently on cellular processes, remains unclear. The Specific Aims outlined in this proposal are designed to provide a more detailed understanding of SUMO- 1 conjugation, its specific effects on protein function, and its more global effects on cellular processes. These goals will be achieved through analysis of the factors and signals regulating SUMO-1 conjugation and deconjugation, characterization of novel SUMO-1 substrates, and characterization of the SUMO-1 related protein, SUMO-2. The hypothesis that SUMO-1 conjugation is regulated by E3-like protein ligases, as well as by deconjugating enzymes, will be investigated. Also, the functional relationships between SUMO-1 conjugation and PML nuclear bodies will be investigated through analysis of BLM, a novel SUMO-1/SUMO-2 substrate, and through analysis of substrates associated with the XY body of pachytene spermatocytes. The hypothesis that the XY body and PML nuclear bodies are functionally related and share common SUMO-1 conjugates will also be investigated.