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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.

生物体的遗传稳定性取决于姐妹染色单体准确划分为两个子代有丝分裂期间的细胞，这反过来又需要维持姐妹之间的物理联系（内聚力）染色单体直到它们双极附着在有丝分裂纺锤体上。去除粘连蛋白（蛋白质复合物，维持姐妹染色单体的凝聚力），然后导致姐妹染色单体分离。在在脊椎动物细胞中，粘连蛋白的去除分两个步骤进行。在前期，大部分粘连蛋白沿染色体臂通过 Polo 样激酶 (Plk1)/Aurora B 依赖性磷酸化被去除凝聚力。在中期，残留的粘连蛋白着丝粒库被分离酶切割，以允许姐妹染色单体分离。我实验室的长期目标是了解其分子机制哺乳动物细胞中的染色体分离。在这个提案中，我们将解决一个有趣的难题区域：着丝粒粘连蛋白如何在前期免受 Plk1 /Aurora B 的作用？我们有最近提供的证据表明纺锤体检查点激酶 Bub1 的目标和 Sgo1 着丝粒蛋白和蛋白磷酸酶 2A (PP2A) 到着丝粒，在那里它们抵消 Plk1 和其他有丝分裂激酶对粘连蛋白进行磷酸化。在具体目标 1 和 2 中，我们将进一步描述 Bub1、Sgo1 和 PP2A 协作保护着丝粒内聚力的机制。在另一方面，我们的结果也表明 Sgo1 具有独立于 PP2A 的作用。事实上，我们已经制作了两本小说以及过去一年的相关发现。 Sgo1 直接与 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。实验是目标 3 和 4 计划确定这些发现的体内相关性。着丝粒过早丢失姐妹染色单体凝聚力导致染色体错误分离和染色体数量异常子细胞（非整倍体），导致癌症形成和出生缺陷。拟议的研究将揭示染色体分离的机制，并可能反过来带来更好的理解以及预防人类癌症和先天缺陷（例如唐氏综合症）中的染色体不稳定和非整倍性综合症。