Mechanisms of Sister Telomere Cohesion and Resolution

描述(由申请人提供)：姐妹端粒的凝聚和分解机制DNA的准确复制和分离对于生命的连续性是必不可少的。染色体分离的错误可能导致非整倍体，并导致体细胞癌症。为了确保染色体准确地分配到子细胞，姐妹染色单体从S期复制时起一直保持在一起，直到有丝分裂时由称为粘附素的蛋白质桥分离。粘附素的解离受两条不同的途径调节，一条作用于染色体臂，另一条作用于着丝粒。我们最近发现了第三条作用于端粒的途径。在缺乏tankyrase 1的细胞中，臂和着丝粒正常分离，但端粒保持联系，导致早期后期停滞。我们的研究表明，复制的、凝聚的端粒独特地需要tankyrase 1及其催化PARP[聚(ADP-核糖)聚合酶]活性来解析它们。这项研究计划的目标是确定将姐妹端粒连接在一起的分子成分，并阐明解决这种联系的机制。为了实现这些目标，我们将(1)描述粘连蛋白与端粒之间的联系，重点是我们新发现的粘附素亚基SA1和端粒亚单位TRF1之间的相互作用，(2)确定凝聚素在解决姐妹端粒凝聚力中的作用，重点是我们新发现的凝聚素I和含有TRF1的端粒复合体之间的相互作用，以及(3)确定姐妹端粒分辨的精确时间和控制。此外，在所有这三个目标中，我们将研究tankyrase 1在姐妹端粒解析中的作用。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粘附素的蛋白质复合体结合在一起。姐妹染色单体凝聚力的错误是人类癌症的主要驱动力。因此，了解管理凝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.