Mechanisms of Sister Telomere Cohesion and Resolution

描述（由申请人提供）：姐妹端粒凝聚和分辨机制DNA的忠实复制和分离是生命延续的必要条件。染色体分离错误可导致非整倍体，并在体细胞中引发癌症。为了确保染色体准确地分配给子细胞，姐妹染色单体从S期复制开始一直保持在一起，直到它们在有丝分裂中通过称为内聚蛋白的蛋白桥分离。黏结蛋白的分离受两种不同途径的调控，一种作用于染色体臂，另一种作用于着丝粒。我们最近发现了第三种途径，它作用于端粒。在坦克酶1缺陷的细胞中，臂和着丝粒正常分离，但端粒保持联系，导致早期晚期停滞。我们的研究表明，复制的、凝聚的端粒独特地需要罐化酶1及其催化的PARP[聚（adp -核糖）聚合酶]活性来进行分解。本研究计划的目标是确定将姐妹端粒结合在一起的分子成分，并阐明解决这种关联的机制。为了实现这些目标，我们将(1)表征黏结蛋白与端粒的关联，重点研究我们新发现的黏结蛋白亚基SA1与端粒亚基TRF1之间的相互作用；(2)确定凝聚蛋白在解决姐妹端粒内聚中的作用，重点研究我们新发现的凝聚蛋白I与含有TRF1的端粒复合物之间的相互作用；(3)确定姐妹端粒内聚的精确时间和控制。此外，在所有三个目标中，我们将研究tankyase 1在姐妹端粒分解中的作用。相关性：为了确保遗传物质准确地传递到子细胞，复制的姐妹染色单体被称为内聚蛋白的蛋白质复合物结合在一起。姐妹染色单体内聚的错误是人类癌症的主要驱动力。因此，了解支配内聚力的机制将与人类疾病高度相关。

DESCRIPTION (provided by applicant): MECHANISMS OF SISTER TELOMERE COHESION AND RESOLUTION Faithful duplication and segregation of DNA are essential for the continuity of life. Errors in chromosome segregation can lead to aneuploidy and drive cancer in somatic cells. To ensure accurate distribution of chromosomes to daughter cells, sister chromatids are held together from the time of their replication in S phase until their separation in mitosis by proteinaceous bridges called cohesins. Dissociation of cohesins is regulated by two distinct pathways, one acting on chromosome arms and the other on centromeres. We have recently discovered a third pathway, which acts on telomeres. In tankyrase 1 deficient cells arms and centromeres separate normally, but telomeres remain associated, resulting in an early anaphase arrest. Our studies suggest that replicated, cohered telomeres uniquely require tankyrase 1 and its catalytic PARP [poly (ADP-ribose) polymerase] activity for their resolution. The goal of this research proposal is to identify the molecular components that hold sister telomeres together and to elucidate the mechanisms that resolve this association. To achieve these goals we will (1) characterize the association of cohesins with telomeres, focusing on our newly identified interaction between the cohesin subunit SA1 and the telomeric subunit TRF1, (2) determine the role of condensins in resolving sister telomere cohesion, focusing on our newly identified interaction between condensin I and the telomeric complex containing TRF1, and (3) determine the precise timing and control of sister telomere resolution. Additionally, in all three aims we will investigate the role of tankyrase 1 in resolution of sister telomeres. Relevance: To ensure accurate transmission of genetic material to daughter cells, replicated sister chromatids are held together by protein complexes called cohesins. Mistakes in sister chromatid cohesion are a major driving force in human cancers. Thus, understanding the mechanisms that govern cohesion will be highly relevant to human disease.