The role of cohesion fatigue in chromosome instability

内聚疲劳在染色体不稳定中的作用

• 批准号: 9266556
• 负责人: GARY J. GORBSKY
• 金额: $ 8.63万
• 依托单位: OKLAHOMA MEDICAL RESEARCH FOUNDATION
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9266556
• 关键词: Affect; Anaphase; Aneuploidy; Area; Binding; Biochemical Pathway; Cell Cycle; Cell Separation; Cell division; Cells; Characteristics; Chromatids; Chromosomal Instability; Chromosome Arm; Chromosome Cohesion; Chromosome Painting; Chromosome Segregation; Chromosome abnormality; Chromosomes; Coin; Complex; Congenital Abnormality; Cytokinesis; DNA Damage; Defect; Equilibrium; Exhibits; Fatigue; Fluorescent Dyes; Generations; Genes; Genetic; Germ Cells; Goals; Health; Human; Human Development; Incidence; Individual; Infertility; Joints; Kinetochores; Lead; Malignant Neoplasms; Mammalian Cell; Maps; Mass Spectrum Analysis; Maternal Age; Mechanics; Medical; Meiosis; Metaphase; Metaphase Plate; Microscopy; Microtubules; Mitosis; Mitotic; Mitotic/Spindle Checkpoint; Molecular; Movement; Mutate; Oncogenic; Oocytes; Optic Chiasm; Pathway interactions; Population; Post-Translational Protein Processing; Predisposing Factor; Predisposition; Process; Proteins; Resistance; Role; Saccharomycetales; Sister Chromatid; Site; Source; Spectral Karyotyping; Stimulus; Stress; Testing; Time; Yeast Model System; Yeasts; age effect; arm; cell transformation; cohesin; cohesion; fluorophore; micronucleus; neoplastic cell; novel therapeutic intervention; older women; premature; protein complex; research study; segregation; tumor; tumorigenesis

DESCRIPTION (provided by applicant): Chromosome instability (CIN) is an important component in several human health problems including cancer, birth defects, and infertility. The Gorbsky lab discovered a new source of CIN that was termed cohesion fatigue. Cohesion fatigue is the progressive, asynchronous separation of sister chromatids in cells delayed at metaphase. The overall goals of this project are to map the downstream consequences of cohesion fatigue, the mechanisms by which chromatids surrender cohesion, and the upstream pathways that modulate the cell sensitivity to cohesion fatigue. In Aim 1, advanced microscopy at both the single cell level and population level will be used to track the chromosome abnormalities that arise from cohesion fatigue. Cohesion fatigue has the potential to simultaneously generate the two types of gross chromosome aberrations that often arise during oncogenesis, changes in whole chromosome number (aneuploidy) and large segmental chromosome duplications, deletions, and translocations. In addition, cohesion fatigue is highly likely to lead to the formation of micronuclei, which have been implicated as sites of massive DNA damage. Aim 2 will determine the mechanisms of cohesin release during cohesion fatigue through experiments that lock individual joints of the cohesin protein complex. In addition, quantitative mass spectrometry will be used to analyze cohesin components that are removed or altered in their post-translational modifications during cohesion fatigue. Aim 3 will map the upstream pathways that regulate sensitivity to cohesion fatigue, concentrating on defects in transformed cells that may exacerbate CIN. Transformed cells often exhibit defects in cell cycle regulators, and cohesion genes are among the most often mutated in human tumors. Thus, transformed cells may be highly susceptible to cohesion fatigue. This aim will test how alterations of cell cycle regulators induce metaphase delays and how these delays synergize with transformation-associated defects in spindle microtubule dynamics and chromosome cohesion to promote cohesion fatigue. Aim 4 extends the analysis of cohesion fatigue to budding yeast to examine the conservation of cohesion fatigue regulators in mitosis and to test specific hypotheses about how cohesion fatigue contributes to premature loss of cohesion between homologous chromosomes during meiosis. Recent evidence implicates decay in chromosome cohesion as a contributor to the maternal age effect, whereby the oocytes of older women show a greatly increased incidence of aneuploidy. In mammalian gametes, cohesion fatigue may be an important causative factor in meiotic aneuploidy, contributing to birth defects and infertility.

描述（由申请人提供）：染色体不稳定性（CIN）是几个人类健康问题的重要组成部分，包括癌症，出生缺陷和不育。 Gorbsky实验室发现了一种新的CIN来源，称为凝聚力疲劳。凝聚力疲劳是在中期延迟的细胞中姐妹染色单体的进行性，异步分离。该项目的总体目标是绘制凝聚力疲劳的下游后果，染色单体投降凝聚力的机制以及调节细胞对凝聚力疲劳敏感性的上游途径。在AIM 1中，单细胞水平和人群水平的晚期显微镜将用于跟踪凝聚力疲劳引起的染色体异常。凝聚力疲劳有可能同时产生两种类型的总染色体畸变，这些染色体畸变经常在肿瘤发生期间出现，整个染色体数（非整倍）的变化和大的分段染色体重复，缺失，缺失和易位。此外，内聚力疲劳极有可能导致形成微核，这已被视为大规模DNA损伤部位。 AIM 2将通过锁定粘着蛋白蛋白复合物的单个关节的实验来确定内聚疲劳期间粘蛋白释放的机制。此外，定量质谱法将用于分析粘质后在粘合疲劳期间的翻译后修饰中去除或改变的粘着蛋白成分。 AIM 3将绘制调节对凝聚力疲劳敏感性的上游途径，集中在可能加剧CIN的转化细胞中的缺陷上。转化的细胞通常在细胞周期调节剂中表现出缺陷，并且内聚力基因是人类肿瘤中最常见的突变。因此，转化的细胞可能高度容易受到内聚力疲劳的影响。该目的将测试细胞周期调节剂的变化如何引起中期延迟，以及这些延迟如何与纺锤微管动力学和染色体凝聚力中与转化相关的缺陷协同作用以促进凝聚力疲劳。 AIM 4将凝聚力疲劳的分析扩展到萌芽的酵母，以检查有丝分裂中凝聚力疲劳调节剂的保存，并测试有关粘连疲劳如何有助于减数分裂过程中同源染色体之间凝聚力过早凝聚力的特定假设。最近的证据暗示染色体内聚力的衰减是孕产妇年龄效应的贡献，因此，老年妇女的卵母细胞显示出非整倍性的发生率大大增加。在哺乳动物的配子中，凝聚力疲劳可能是减数分裂性非整倍性的重要原因因素，导致了先天缺陷和不育。