Investigate the molecular mechanism that ensures chromosome bipolar attachment

研究确保染色体双极附着的分子机制

• 批准号: 9135454
• 负责人: Yanchang Wang
• 金额: $ 24.88万
• 依托单位: FLORIDA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-30 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9135454
• 关键词: Address; Anaphase; Aneuploid Cells; Aneuploidy; Binding; Cancer Etiology; Cell Cycle; Cells; Chromosome Segregation; Chromosomes; Complex; Congenital Abnormality; Data; Defect; Docking; Elements; Ensure; Event; Failure; Generations; Genome Stability; Genomic Instability; Goals; Health; Hereditary Disease; Kinetochores; Link; Malignant Neoplasms; Methods; Microtubules; Mitosis; Molecular; Outcome; Pathway interactions; Phosphorylation; Phosphotransferases; Process; Protein Dephosphorylation; Protein phosphatase; Proteins; Regulation; Research; Role; Saccharomycetales; Signal Transduction; Sister; Sister Chromatid; Site; Testing; Time; Work; abstracting; aurora kinase; cancer diagnosis; cancer prevention; cancer therapy; chromosome loss; daughter cell; innovation; live cell imaging; mutant; premature; prevent; segregation

DESCRIPTION (provided by applicant): Project Summary/Abstract: Accurate chromosome segregation depends on the establishment of bipolar attachment, whereby sister kinetochores are attached to microtubules from opposite spindle poles. Failure of bipolar attachment will generate aneuploid cells, which directly contributes to genetic disorders, such as cancer and birth defects. Incorrect chromosome attachments are sensed by the spindle assembly checkpoint (SAC) that delays anaphase onset to allow error-correction. Once cells have established chromosome bipolar attachments, the checkpoint has to be silenced to allow anaphase onset, but little is known about the molecular mechanism for SAC silencing. The objective of this application is to uncover and characterize the SAC silencing network (SSN). We hypothesize that the SSN coordinates error sensing, error-correction, and SAC silencing to ensure chromosome bipolar attachment prior to anaphase onset. This proposal is innovative as it will uncover the poorly uncharacterized signaling cascade SSN that is critical for faithful chromosome segregation. The completion of this research will provide the first detailed view for SAC silencing process. This research will be significant because the identified new components in the SSN will uncover new targets for cancer diagnosis and prevention.

描述(由申请人提供)： 项目摘要/摘要：准确的染色体分离依赖于两极连接的建立，即姐妹着丝点从相反的纺锤体极连接到微管上。两极连接的失败将产生非整倍体细胞，这直接导致遗传疾病，如癌症和出生缺陷。纺锤体组件检查点(SAC)检测到不正确的染色体附着，延迟后期开始，以便进行纠错。一旦细胞建立了染色体双极连接，检查点就必须被沉默，以便后期开始，但对SAC沉默的分子机制知之甚少。此应用程序的目标是发现SAC沉默网络(SSN)并对其进行描述。我们假设SSN协调错误检测、错误纠正和SAC沉默，以确保在后期开始之前染色体双极附着。这一建议是创新的，因为它将揭示对忠实的染色体分离至关重要的未被描述的信号级联SSN。这项研究的完成将为SAC沉默过程提供第一个详细的视角。这项研究将是 意义重大，因为SSN中已识别的新成分将发现癌症诊断和预防的新靶点。

项目成果

Identification of a novel Polo-like kinase 1 inhibitor that specifically blocks the functions of Polo-Box domain.

鉴定出一种新型 Polo 样激酶 1 抑制剂，可特异性阻断 Polo-Box 结构域的功能。

• DOI: 10.18632/oncotarget.13603
• 发表时间: 2017-01-03
• 期刊: Oncotarget
• 作者: Chen Y;Zhang J;Li D;Jiang J;Wang Y;Si S
• 通讯作者: Si S

Ubiquilin/Dsk2 promotes inclusion body formation and vacuole (lysosome)-mediated disposal of mutated huntingtin.

• DOI: 10.1091/mbc.e16-01-0026
• 发表时间: 2016-07-01
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Chuang KH;Liang F;Higgins R;Wang Y
• 通讯作者: Wang Y

The absence of specific yeast heat-shock proteins leads to abnormal aggregation and compromised autophagic clearance of mutant Huntingtin proteins.

缺乏特定的酵母热蛋白会导致异常聚集，并损害突变体亨廷汀蛋白的自噬清除率。

• DOI: 10.1371/journal.pone.0191490
• 发表时间: 2018
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Higgins R;Kabbaj MH;Hatcher A;Wang Y
• 通讯作者: Wang Y

Yeast Fin1-PP1 dephosphorylates an Ipl1 substrate, Ndc80, to remove Bub1-Bub3 checkpoint proteins from the kinetochore during anaphase.

• DOI: 10.1371/journal.pgen.1009592
• 发表时间: 2021-05
• 期刊: PLoS genetics
• 影响因子: 4.5
• 作者: Bokros M;Sherwin D;Kabbaj MH;Wang Y
• 通讯作者: Wang Y

Premature Silencing of the Spindle Assembly Checkpoint Is Prevented by the Bub1-H2A-Sgo1-PP2A Axis in Saccharomyces cerevisiae.

酿酒酵母中的 Bub1-H2A-Sgo1-PP2A 轴可防止主轴装配检查点的过早沉默。

• DOI: 10.1534/genetics.116.195727
• 发表时间: 2017
• 期刊: Genetics
• 影响因子: 3.3
• 作者: Jin,Fengzhi;Bokros,Michael;Wang,Yanchang
• 通讯作者: Wang,Yanchang