Mechanisms of Sister Chromatid Pairing

姐妹染色单体配对机制

基本信息

批准号：
8036701
负责人：
ROBERT SKIBBENS
金额：
$ 30万
依托单位：
LEHIGH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-03-01 至 2013-09-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): To produce viable progeny, cells must identify the products of chromosome replication as sister chromatids from S-phase until chromosome segregation. Sister chromatid identity is achieved by a combination of complexes: 1) cohesin tethers that maintain pairing over time, 2) deposition factors that load cohesins onto sister chromatids and 3) establishment factors that convert chromatin-associated cohesins into a paired or tethered state. All of these cohesion pathways are essential such that mutation in any one (maintenance, deposition and establishment) results in massive chromosome mis-segregation and cell death. Many of the phenotypes observed in cohesion loss mutants (aneuploidy, genome instability, defects in DNA repair, hyper- recombination and chromosomal translocations) are direct consequences of precocious sister separation and loss of a repair template - all hallmarks of cancer cells. More recent findings reveal a surprising link between cohesion defects and developmental abnormalities that include Cornelia de Lange Syndrome and Roberts Syndrome/SC Phocomelia. At the molecular level, the first establishment model posited in the literature suggested that cohesin complexes associated with each sister become tethered together through an active process that is intimately coupled to the DNA replication fork. Findings from several labs confirm the link between the establishment factor (Ctf7/Eco1) and numerous DNA replication components that include PCNA, RFC factors, and DNA helicases. Moreover, recent reports provide important clues regarding Ctf7/Eco1 acetylation-dependent conversion of cohesins to a pairing competent state and how precocious conversion (pairing) is blocked by anti-establishment factors. The Specific Aims of this R15 AREA proposal test new models of establishment by focusing on the role of both pro- and anti- establishment DNA replication factors in cohesion acetylation reactions. In addition, we test models regarding chromatin recruitment and activation of the essential establishment factor Ctf7/Eco1.) PUBLIC HEALTH RELEVANCE: Chromosomes contain the instruction manual for cells and organisms to grow and develop. For growth during embryonic development, in response to trauma or to replace cells in a harsh environment (gastro-intestinal tracts), cells must replicate their chromosomes and then divide such that each daughter cell gets an identical copy. This proposal explores new models regarding how these replicated chromosomes are properly segregated during cell division.

描述（由申请人提供）：为了产生可行的后代，细胞必须将复制的产物识别为从S期染色单体直至染色体分离的姐妹染色单体。姐妹染色质身份是通过复合物的组合来实现的：1）粘合素二粘着蛋白质的粘合素三颗粒，2）沉积因子将凝聚在姐妹染色质上的沉积因子和3）将染色质相关粘连转化为配对或绑扎状态的建立因子。所有这些内聚力途径都是必不可少的，使得任何一个突变（维持，沉积和建立）会导致大量的染色体错误分离和细胞死亡。在内聚损失突变体（非整倍性，基因组不稳定性，DNA修复中的缺陷，超重组和染色体易位的缺陷）中观察到的许多表型是早熟姐妹分离和修复模板丢失的直接后果 - 癌细胞的所有特征。最近的发现表明，内聚力缺陷与发育异常之间存在令人惊讶的联系，包括Cornelia de Lange综合征和Roberts综合征/SC Phocomelia。在分子水平上，文献中提出的第一个机构模型表明，与每个姐妹相关的粘蛋白复合物通过与DNA复制叉密切耦合的活跃过程束缚在一起。来自多个实验室的发现证实了建立因子（CTF7/ECO1）与包括PCNA，RFC因子和DNA解旋酶在内的许多DNA复制组件之间的联系。此外，最近的报告提供了有关CTF7/ECO1乙酰化依赖性粘连转化为配对胜任状态的重要线索以及如何被抗建筑因素阻止的早熟转换（配对）。该R15区域提案的具体目的测试了新的建立模型，该模型通过关注促和抗建立的DNA复制因子在凝聚力乙酰化反应中的作用。此外，我们测试了有关基本建立因子CTF7/ECO1的染色质募集和激活的模型。）公共卫生相关性：染色体包含有关细胞和生物生长和发育的说明手册。为了在胚胎发育过程中生长，响应创伤或在恶劣的环境中替代细胞（胃肠道），细胞必须复制其染色体，然后分裂，以使每个子细胞获得相同的副本。该建议探讨了有关在细胞分裂过程中如何正确隔离这些复制染色体的新模型。