Mechanisms of Sister Telomere Cohesion and Resolution

描述(由申请人提供)： 本研究计划的目的是阐明人类细胞中姐妹端粒凝聚力的调节机制。端粒是一种独特的异染色质结构，需要特殊的机制来进行复制、保护和凝聚。S期姊妹端粒间粘附性的建立是细胞周期G2期同源重组和DNA修复所必需的，而有丝分裂时姐妹端粒间粘附性的及时解决对基因组的完整性至关重要。我们在人类细胞中的研究表明，姐妹端粒需要不同的机制(与姐妹臂和着丝粒相比)，以建立S阶段的凝聚力和分解有丝分裂。在这里，我们试图阐明潜在的机制。在目标1中，我们将确定端粒是如何建立凝聚力的，以及为什么它很重要。在目标2中，我们将确定如何在有丝分裂时从端粒中去除凝聚力，以及如果不是这样会发生什么。在目标3中，我们将探索一个新的假设(基于我们的新的初步数据)，即有丝分裂时的持续凝聚力是处理端粒功能障碍的一般细胞机制。好了！ 公共卫生相关性： 项目叙事端粒是染色体的末端，对染色体的稳定性和基因组完整性起着至关重要的作用。端粒功能障碍会导致衰老、癌症和其他人类疾病，包括先天性角化不良和遗传性骨髓衰竭疾病。该项目的结果将揭示端粒功能是如何在人类细胞中保持的，从而影响我们对人类疾病的理解，并有助于癌症和衰老的治疗。

DESCRIPTION (provided by applicant): Project Summary The goal of this research proposal is to elucidate the mechanisms that regulate sister telomere cohesion in human cells. Telomeres are unique heterochromatic structures that require specialized mechanisms for their replication, protection, and cohesion. Establishment of cohesion between sister telomeres in S phase is essential for homologous recombination and DNA repair in G2 phase of the cell cycle and timely resolution of cohesion between sister telomeres at mitosis is critical for genome integrity. Our studies in human cells have shown that sister telomeres require distinct mechanisms (compared to sister arms and centromeres) for cohesion establishment in S phase and resolution in mitosis. Here we seek to elucidate the underlying mechanisms. In Aim 1 we will determine how cohesion is established at telomeres and why it is important. In Aim 2 we will determine how cohesion is removed from telomeres at mitosis and what happens if it is not. And in Aim 3 we will explore a novel hypothesis (based upon our new preliminary data) that persistent cohesion at mitosis is a general cellular mechanism for dealing with telomere dysfunction. ! PUBLIC HEALTH RELEVANCE: Project Narrative Telomeres, the ends of chromosomes, play a crucial role in chromosome stability and genome integrity. Telomere dysfunction contributes to aging, cancer, and other human diseases, including dyskeratosis congenital an inherited bone marrow failure disease. The results from this project will reveal how telomere function is maintained in human cells and will thus impact our understanding of human disease and contribute to therapeutics in cancer and aging.