Regulation and Function of SUMO Protein Modification

 描述（由申请方提供）：类小泛素化对染色体分离至关重要;它是中期平板上染色体对齐以及中期到后期过渡时姐妹染色单体分离所必需的。这些过程中的缺陷可能导致错误的染色体分离，这与人类癌症和遗传疾病的发展有关。SUMO化通过有丝分裂控制进程的分子机制仍然知之甚少。特别是，被修饰以影响控制的蛋白质在很大程度上是未知的，并且调节其空间和时间修饰和去修饰的机制也不清楚。为了解决这些问题，我们将建立在我们最近发现的SUMO蛋白酶，SENP 1，控制从中期到后期的进展，通过调节纺锤体组装检查点的失活和/或后期促进复合物/细胞周期体的激活。我们提出的研究的目标是确定SUMO化调节后期发作的分子机制，并确定SENP 1如何影响有丝分裂中SUMO化的精确空间和时间控制。该提案的目的包括：（1）确定SENP 1和类小泛素化在调控后期启动中的作用，（2）确定SENP 1定位、磷酸化和有丝分裂功能之间的关系，（3）鉴定SENP 1底物并确定定位和磷酸化如何影响底物选择性。

 DESCRIPTION (provided by applicant): Sumoylation is essential for chromosome segregation; it is required for alignment of chromosomes at the metaphase plate, and for separation of sister chromatids at the metaphase to anaphase transition. Defects in these processes can lead to erroneous chromosome segregation, which is linked to development of human cancers and genetic diseases. The molecular mechanisms by which sumoylation controls progression through mitosis remain poorly understood. In particular, the proteins that are modified to affect control are largely unknown, and the mechanisms that regulate their spatial and temporal modification and demodification are also unclear. To address these issues, we will build on our recent discovery that the SUMO protease, SENP1, controls the progression from metaphase to anaphase by regulating inactivation of the spindle assembly checkpoint and/or activation of the anaphase promoting complex/cyclosome. The goals of our proposed studies are to define the molecular mechanisms by which sumoylation regulates anaphase onset and to determine how SENP1 affects precise spatial and temporal control of sumoylation in mitosis. Aims of the proposal include: (1) Defining the roles of SENP1 and sumoylation in regulating anaphase onset, (2) Defining the relationships between SENP1 localization, phosphorylation and mitotic function, and (3) Identifying SENP1 substrates and defining how localization and phosphorylation affect substrate selectivity.