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：
7322876
负责人：
HONGTAO YU
金额：
$ 29.83万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-08-10 至 2011-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7322876
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 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 Localized Maintenance Malignant Neoplasms Mammalian Cell Mediating Meiosis Metaphase Methods Mitosis Mitotic Mitotic spindle Molecular Mutation Nucleic Acid Binding Numbers 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 programs reconstitution research study separase tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): 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 (the protein 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 Plk1 and 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.

描述（由申请人提供）：生物的遗传稳定性取决于有丝分裂过程中姐妹染色单体的准确分配到两个子细胞中，这反过来又需要维持姊妹染色质剂之间的物理链接（粘合剂），直到它们的双极性附着在有丝分裂夹克上。从染色体中去除粘着蛋白（维持姐妹染色质凝聚的蛋白质复合物），然后导致姐妹染色单体分离。在脊椎动物细胞中，去除粘蛋白分为两个步骤。在预言中，沿着染色体臂的大多数粘着蛋白通过粘蛋白的polo样激酶（PLK1）/Aurora B依赖性磷酸化去除。在中期，残留的粘着蛋白的丝粒池通过分离酶切割，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染色体分离的分子机制。在此提案中，我们将在该领域讨论一个有趣的难题：centromeric凝聚素如何避免PLK1 /Aurora B在预言中的作用？我们最近提供了证据表明，纺锤体检查点激酶BUB1靶标以及SGO1丝粒蛋白和蛋白质磷酸酶2a（PP2A）对centromeres centromeres来抵消PLK1和其他有丝分裂激酶的黏附蛋白的磷酸化。在特定目标1和2中，我们将进一步描述BUB1，SGO1和PP2A合作以保护中心粒子凝聚力的机制。另一方面，我们的结果还指出了SGO1独立于PP2A的作用。确实，在过去的一年中，我们做出了两个小说和相关的发现。 SGO1直接与称为ILF2-ILF3（白介素增强子结合因子2和3）的RNA结合蛋白复合物相互作用。 SGO1本身在体外与RNA结合。计划在目标3和4中进行实验，以建立这些发现的体内相关性。丝粒姐妹染色质被的过早损失导致子细胞中染色体的染色体错误分析和异常数量，这有助于癌症形成和先天缺陷。拟议的研究将阐明染色体隔离的机制，进而可能导致对人类癌症和先天缺陷（例如唐氏综合症）的染色体不稳定性和非整倍性更好地理解和预防。