Protection of Centromeric Cohesion by Bub1 and Sgo1
Protection of Centromeric Cohesion by Bub1 and Sgo1
批准号:
7883728
负责人:
HONGTAO YU
金额:
$28.09万
依托单位国家:
美国
项目类别:
财政年份:
2009
资助国家:
美国
项目状态:
已结题
起止时间:
2009-08-10 至 2012-05-31
关键词:
45-kDa nuclear factor of activated T-cellsAddressAdoptedAffinityAneuploidyAreaBindingBinding ProteinsBiochemicalBiological AssayC-terminalCellsCentromereChromosomal InstabilityChromosome ArmChromosome CohesionChromosome SegregationChromosomesClassificationCleaved cellComplexCongenital AbnormalityDouble-Stranded RNADown SyndromeElectrophoretic Mobility Shift AssayEvolutionExcisionFission YeastGeneticGenetic MaterialsGoalsHandHela CellsHeterochromatinHumanIn VitroKinetochoresLeadLigandsLigaseLightMaintenanceMalignant NeoplasmsMammalian CellMediatingMeiosisMetaphaseMethodsMitosisMitoticMitotic spindleMolecularMutationNucleic Acid BindingOrganismPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphorylation SitePhosphotransferasesPlayPolynucleotide AdenylyltransferasePrecipitationPreventionProcessProphaseProtein DephosphorylationProtein FamilyProtein phosphataseProteinsRNARNA BindingRNA InterferenceRNA Interference PathwayRNA-Binding ProteinsRecombinantsRecruitment ActivityResearchResearch PersonnelResidual stateRoleSister ChromatidStructureTestingTransferaseUbiquitinationYeastscohesincohesioncrosslinkdaughter cellheterochromatin-specific nonhistone chromosomal protein HP-1human PLK1 proteinin vivoinsightinterestmanmutantnoveloligoadenylateprematureprogramsprotein complexreconstitutionresearch studyseparasetumorigenesis
中文摘要
一个生物体的遗传稳定性依赖于姐妹染色单体准确地划分为两个子代
细胞在有丝分裂过程中,这反过来又需要维持姐妹之间的物理联系(凝聚力)。
染色单体直到它们的两极附着在有丝分裂的纺锤体上。去除粘连蛋白(蛋白复合物,
保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,粘附素的去除分两步进行。在前期,大部分的粘结剂沿着沿着
染色体臂通过Polo样激酶(Plk 1)/Aurora B依赖性磷酸化被去除,
黏连蛋白在中期,残留的着丝粒池的粘连蛋白被切割分离酶,使姐妹
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。在这个建议中,我们将解决一个有趣的难题,
区域:在前期,着丝粒粘附蛋白如何被Plk 1/Aurora B的作用屏蔽?我们有
最近提供的证据表明,纺锤体检查点激酶Bub 1的目标和Sgo 1
着丝粒蛋白和蛋白磷酸酶2A(PP 2A)到着丝粒,在那里它们抵消了
Plk 1和其他有丝分裂激酶对粘着蛋白的磷酸化。在具体目标1和2中,我们将进一步
描述了Bub 1,Sgo 1和PP 2A合作保护着丝粒凝聚力的机制。对
另一方面,我们的研究结果也指出了一个PP 2A独立的Sgo 1的作用。我确已创造了两个新的
及相关调查结果。Sgo 1直接与RNA结合蛋白复合物相互作用,
ILF 2-ILF 3(白细胞介素增强子结合因子2和3)。Sgo 1本身在体外与RNA结合。实验
目的3和4中计划的,以确定这些发现的体内相关性。着丝粒过早丢失
姐妹染色单体凝聚导致染色体错误分离和染色体数目异常,
子细胞(非整倍体),这有助于癌症形成和出生缺陷。拟议研究
将揭示染色体分离的机制,并可能反过来导致更好的理解
以及预防人类癌症和出生缺陷中的染色体不稳定性和非整倍性,例如Down
综合征
英文摘要
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.
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