Mechanisms of Sister Telomere Cohesion and Resolution

描述（申请人提供）：姐妹端粒的凝聚和分辨率的机制DNA的忠实复制和分离对于生命的连续性至关重要。染色体分离的错误可导致非整倍性并在体细胞中驱动癌症。为了确保染色体准确地分配给子细胞，姐妹染色单体从它们在S期复制的时间到它们在有丝分裂中通过称为粘着蛋白的蛋白质桥分离的时间保持在一起。粘连蛋白的解离受两种不同的途径调节，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。在端锚聚合酶1缺陷的细胞中，臂和着丝粒正常分离，但端粒保持相关，导致早期后期停滞。我们的研究表明，复制，凝聚端粒独特地需要端锚聚合酶1和其催化PARP [聚（ADP-核糖）聚合酶]的活动，他们的决议。这项研究计划的目标是确定将姐妹端粒保持在一起的分子组分，并阐明解决这种关联的机制。为了实现这些目标，我们将（1）表征粘着蛋白与端粒的关联，重点是我们新鉴定的粘着蛋白亚基SA 1和端粒亚基TRF 1之间的相互作用，（2）确定凝聚蛋白在解析姐妹端粒粘着中的作用，重点是我们新鉴定的凝聚蛋白I和含有TRF 1的端粒复合物之间的相互作用，以及（3）确定姐妹端粒解析的精确时间和控制。此外，在所有三个目标中，我们将研究端锚聚合酶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通过称为粘着蛋白的蛋白质复合物保持在一起。姐妹染色单体内聚的错误是人类癌症的主要驱动力。因此，了解控制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.