Regulation of chromosome segregation

染色体分离的调控

基本信息

批准号：
8136707
负责人：
DAVID Owen MORGAN
金额：
$ 29.06万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-01 至 2014-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8136707
关键词：
Address Anaphase Behavior Biochemical Biochemical Reaction Cancer Etiology Cells Centromere Chromosome Arm Chromosome Segregation Chromosomes Complex Defect Development Disease Event Feedback Genetic Goals In Vitro Kinetics Knowledge Lead Life Link Malignant Neoplasms Measures Metaphase Microscopy Mitosis Mitotic spindle Molecular Movement Output Peptide Hydrolases Phosphoric Monoester Hydrolases Phosphorylation Process Protein Dephosphorylation Protein Kinase Protein phosphatase Regulation Relative (related person)Research S Phase Saccharomyces cerevisiae Saccharomycetales Sister Sister Chromatid System Testing Time Work Yeasts anaphase-promoting complex assay development cohesin daughter cell human PLK1 protein human PTTG1 protein human disease insight protein complex public health relevance reconstitution research study separase single cell analysis tool tumor progression tumorigenesis ubiquitin ligase

项目摘要

DESCRIPTION (provided by applicant): The project will explore the regulatory system that controls the initiation of chromosome separation, a critical event in the life of the cell and an event that often goes awry during tumorigenesis. Following duplication of the chromosomes in S phase of the cell cycle, the resulting sister chromatids are linked together by a protein complex called cohesin. During mitosis, the sister-chromatid pairs are oriented on the bipolar mitotic spindle. At the metaphase-anaphase transition, the cohesin linkage between sister's chromatids is abruptly dissolved by a protease called separase, resulting in synchronous separation of sister chromatids and their movement to opposite poles of the spindle. The proposed studies will explore the control of sister-chromatid separation in the budding yeast Saccharomyces cerevisiae, where much of our knowledge of this process was first uncovered. A key goal of the work will be to identify and characterize the regulatory mechanisms that generate the remarkably robust, switch-like behavior of the anaphase regulatory system. In preliminary studies with yeast cells carrying fluorescent tags on two chromosomes, the synchrony of sister-chromatid separation was found to depend in part on a positive feedback loop that governs activation of separase. These studies also led to the discovery that Chromosome IV consistently separates before Chromosome V, suggesting that chromosomes separate in a specific sequence. The first aim of the proposed studies will be to further characterize synchrony and order in the separation of multiple chromosomes in yeast, and to address the general mechanisms underlying the ordered separation of different chromosomes. The second aim will be to reconstitute the biochemical steps of sister-chromatid separation from purified components, allowing detailed studies of separase activation and cohesin cleavage in vitro. Finally, the third aim will be to use these cellular and biochemical tools to address the mechanisms governing separase activity toward cohesin, with an emphasis on the regulation of cohesin cleavage by protein kinases and phosphatases that control cohesin phosphorylation. The knowledge gained from these studies will provide new insights into the control of chromosome segregation - errors in which often contribute to developmental problems and cancer progression. PUBLIC HEALTH RELEVANCE: When a cell reproduces, the chromosomes are first duplicated and then segregated into a pair of daughter cells. Errors in this process can result in genetic damage or defects in chromosome number, which can accelerate cancer progression or cause developmental defects. The proposed studies focus on the regulatory system that controls the initiation of chromosome separation, with an emphasis on the mechanisms underlying the remarkable robustness and accuracy of this system. These studies will lead to a better understanding of how errors in chromosome segregation can arise in human disease.

描述（由申请人提供）：该项目将探索控制染色体分离启动的调控系统，染色体分离是细胞生命中的一个关键事件，也是肿瘤发生过程中经常出错的事件。在细胞周期 S 期染色体复制后，产生的姐妹染色单体通过称为粘连蛋白的蛋白质复合物连接在一起。在有丝分裂期间，姐妹染色单体对在双极有丝分裂纺锤体上定向。在中期-后期转变时，姐妹染色单体之间的粘连蛋白突然被一种称为分离酶的蛋白酶溶解，导致姐妹染色单体同步分离并移动到纺锤体的相反两极。拟议的研究将探索芽殖酵母酿酒酵母中姐妹染色单体分离的控制，我们对此过程的大部分知识都是首次发现的。这项工作的一个关键目标是识别和表征产生后期调节系统非常强大的、类似开关行为的调节机制。在对两条染色体上携带荧光标签的酵母细胞进行的初步研究中，发现姐妹染色单体分离的同步部分取决于控制分离酶激活的正反馈环。这些研究还发现，第四号染色体始终先于第五号染色体分离，这表明染色体以特定序列分离。拟议研究的首要目标是进一步表征酵母中多个染色体分离的同步性和顺序，并解决不同染色体有序分离的一般机制。第二个目标是重建从纯化组分中分离姐妹染色单体的生化步骤，从而可以在体外详细研究分离酶激活和粘连蛋白裂解。最后，第三个目标是利用这些细胞和生化工具来解决控制粘连蛋白分离酶活性的机制，重点是控制粘连蛋白磷酸化的蛋白激酶和磷酸酶对粘连蛋白裂解的调节。从这些研究中获得的知识将为染色体分离的控制提供新的见解，这种错误往往会导致发育问题和癌症进展。公共健康相关性：当细胞繁殖时，染色体首先复制，然后分离成一对子细胞。此过程中的错误可能会导致遗传损伤或染色体数量缺陷，从而加速癌症进展或导致发育缺陷。拟议的研究重点是控制染色体分离启动的调控系统，重点是该系统卓越的稳健性和准确性背后的机制。这些研究将有助于更好地了解染色体分离错误如何在人类疾病中出现。