Protection of Centromeric Cohesion by Bub1 and Sgo1

Bub1 和 Sgo1 对着丝粒凝聚力的保护

基本信息

批准号：
7883728
负责人：
HONGTAO YU
金额：
$ 28.09万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-08-10 至 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7883728
关键词：
45-kDa nuclear factor of activated T-cells Address Adopted Affinity Aneuploidy Area Binding Binding Proteins Biochemical Biological Assay C-terminal Cells Centromere Chromosomal Instability Chromosome Arm Chromosome Cohesion Chromosome Segregation Chromosomes Classification Cleaved cell Complex Congenital Abnormality Double-Stranded RNA Down Syndrome Electrophoretic Mobility Shift Assay Evolution Excision Fission Yeast Genetic Genetic Materials Goals Hand Hela Cells Heterochromatin Human In Vitro Kinetochores Lead Ligands Ligase Light Maintenance Malignant Neoplasms Mammalian Cell Mediating Meiosis Metaphase Methods Mitosis Mitotic Mitotic spindle Molecular Mutation Nucleic Acid Binding Organism Phenotype Phosphoric Monoester Hydrolases Phosphorylation Phosphorylation Site Phosphotransferases Play Polynucleotide Adenylyltransferase Precipitation Prevention Process Prophase Protein Dephosphorylation Protein Family Protein phosphatase Proteins RNA RNA Binding RNA Interference RNA Interference Pathway RNA-Binding Proteins Recombinants Recruitment Activity Research Research Personnel Residual state Role Sister Chromatid Structure Testing Transferase Ubiquitination Yeasts cohesin cohesion crosslink daughter cell heterochromatin-specific nonhistone chromosomal protein HP-1 human PLK1 protein in vivo insight interest man mutant novel oligoadenylate premature programs protein complex reconstitution research study separase tumorigenesis

项目摘要

The genetic stability of an organism depends on the accurate partition of sister chromatids into two daughter cells during mitosis, which in turn requires the maintenance of the physical linkage (cohesion) between sister chromatids until their bipolar attachment to the mitotic spindle. Removal of cohesin (theprotein complex that maintains sister chromatid cohesion) from chromosomes then leads to sister chromatid separation. In vertebrate cells, removal of cohesin occurs in two steps. At prophase, most of cohesin along the chromosome arms is removed through Polo-like kinase (Plk1)/Aurora B-dependent phosphorylation of cohesin. At metaphase, the residual centromeric pool of cohesin is cleaved by separase to allow sister chromatid separation. The long-term goal of my lab is to understand the molecular mechanism of chromosome segregation in mammalian cells. In this proposal, we will address an interesting puzzle in this area: how is the centromeric cohesin shielded from the actions of Plk1 /Aurora B in prophase? We have recently provided evidence to suggest that the spindle checkpoint kinase Bub1 targets and the Sgo1 centromeric protein and protein phosphatase 2A (PP2A) to centromeres where they counteract the phosphorylation of cohesin by Plk1and other mitotic kinases. In Specific Aims 1 and 2, we will further delineate the mechanisms by which Bub1, Sgo1, and PP2A collaborate to protect centromeric cohesion. On the other hand, our results also point to a PP2A-independent role of Sgo1. Indeed, we have made two novel and related findings in the past year. Sgo1 directly interacts with an RNA-binding protein complex called ILF2-ILF3 (interleukin enhancer binding factors 2 and 3). Sgo1 itself binds to RNA in vitro. Experiments are planned in Aims 3 and 4 to establish the in vivo relevance of these findings. Premature loss of centromeric sister chromatid cohesion leads to chromosome missegregation and abnormal numbers of chromosomes in daughter cells (aneuploidy), which contributes to cancer formation and birth defects. The proposed research will shed light on the mechanism of chromosome segregation and may in turn lead to better understanding and prevention of chromosomal instability and aneuploidy in human cancers and birth defects, such as Down Syndrome.

生物的遗传稳定性取决于姐妹染色单体的准确分区有丝分裂过程中的细胞，这反过染色单体直至其双极连接到有丝分裂主轴上。去除粘着蛋白（蛋白质复合物从染色体中维持姐妹染色单体内聚力），然后导致姐妹染色单体分离。在脊椎动物细胞，去除粘蛋白分为两个步骤。在预言，沿着大多数粘着蛋白染色体臂通过polo样激酶（PLK1）/Aurora B依赖性磷酸化去除粘着蛋白。在中期，残留的粘着蛋白的丝粒池被分离酶裂解以允许姐妹染色单体分离。我实验室的长期目标是了解哺乳动物细胞中的染色体分离。在此提案中，我们将解决这个有趣的难题区域：centromeric粘连如何避免先前PLK1 /Aurora B的作用？我们有最近提供了证据表明主轴检查点激酶BUB1靶标和SGO1 丝粒蛋白质和蛋白质磷酸酶2a（PP2A）到centromeres，它们抵抗了它们 PLK1和其他有丝分裂激酶对粘着蛋白的磷酸化。在特定目标1和2中，我们将进一步描述BUB1，SGO1和PP2A协作以保护丝粒凝聚力的机制。在另一方面，我们的结果也表明了SGO1的pp2a无关作用。确实，我们做了两本小说以及过去一年的相关发现。 SGO1直接与称为RNA结合蛋白复合物相互作用 ILF2-ILF3（白介素增强子结合因子2和3）。 SGO1本身在体外与RNA结合。实验是计划在目标3和4中建立这些发现的体内相关性。过早的丝粒损失姐妹染色单体的内聚力导致染色体错误分析和异常的染色体数量子细胞（非整倍性），这有助于癌症形成和先天缺陷。拟议的研究会阐明染色体隔离的机理，进而可能导致更好的理解预防人类癌症和先天缺陷中的染色体不稳定性和非整倍性（例如综合征。