Regulation of telomere recombination in ALT cancer cells

ALT 癌细胞端粒重组的调控

• 批准号: 9748731
• 负责人: SUSAN SMITH
• 金额: $ 0.28万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9748731
• 关键词: ATRX gene; Aging; Cell Aging; Cell Line; Cell division; Cells; Childhood Glioblastoma; Chromatids; Chromatin Remodeling Factor; Chromosomes; DNA; Data; Enzymes; Event; Fibroblasts; Genetic Recombination; Growth; Hela Cells; Human; Impairment; Link; Malignant Neoplasms; Mediating; Mitosis; Molecular; Pathway interactions; Phenotype; Process; Proteins; Regulation; Reporting; Resolution; Role; Seeds; Simian virus 40; Sister; Tankyrase; Telomerase; Telomere Length Maintenance; Telomere Maintenance; Telomere Recombination; Tumor Cell Line; Up-Regulation; anti-cancer; base; cancer cell; cancer therapy; cell growth; cohesin; cohesion; follow-up; insight; neoplastic cell; novel; overexpression; prevent; recombinational repair; telomere; telomere loss; tumor

Project Summary The unlimited replicative capacity of human tumor cells relies on their ability to counteract the progressive loss of telomeric DNA that accompanies cell division. Eighty- five percent of cancers achieve this by up-regulating telomerase, the enzyme that adds telomere repeats to chromosome ends. The remaining 15% activate ALT (alternative lengthening of telomeres), a recombination-based mechanism. The observation that ALT is activated in a significant fraction of human tumors, combined with the notion that it may provide an adaptive mechanism to anti-telomerase therapies, indicate it as an important target for anti-cancer strategies. Recent studies identified the chromatin- remodeling factor ATRX as the protein most frequently lost in ALT, but how this loss impacts telomere recombination is not known. Our studies reveal a mechanism: loss of ATRX suppresses resolution of sister telomere cohesion at mitosis. The resulting persistent telomere cohesion promotes chromatid exchange between sister telomeres, while it suppresses inappropriate recombination between non-sisters. We hypothesize that persistent telomere cohesion is a critical component of the ALT cell state. In Aim 1 we will elucidate the mechanisms by which loss of ATRX promotes ALT cell recombination and growth. In Aim 2 we will investigate how loss of ATRX leads to activation of ALT. In Aim 3 we will explore the hypothesis that up-regulation of the cohesin subunit SA1 in tumors promotes persistent telomere cohesion and an ALT-like mechanism of telomere maintenance. Understanding how recombination mediates telomere length maintenance in ALT cancers will provide insights into basic mechanisms of recombination as well as provide targets for anti-cancer therapies.

项目摘要 人类肿瘤细胞的无限复制能力取决于其能力 抵消伴随细胞分裂的端粒DNA的进行性损失。八十- 5％的癌症是通过上调端粒酶（添加的酶）来实现这一目标的 端粒重复染色体末端。其余15％激活ALT（替代 端粒的延长），一种基于重组的机制。 Alt的观察 在大量的人类肿瘤中被激活，并结合这样的观念 可以提供对抗细胞瘤疗法的自适应机制，将其表示为 反癌策略的重要目标。最近的研究确定了染色质 - 重塑因子ATRX是最常见的蛋白质，但这种损失是如何丢失的 影响端粒重组尚不清楚。我们的研究揭示了一种机制：丢失 ATRX抑制了有丝分裂的姐妹端粒凝聚力的分辨率。结果 持续的端粒凝聚力促进姐妹端粒之间的染色单体交换， 虽然它抑制了非姐妹之间的不当重组。我们假设 持续的端粒凝聚力是ALT细胞状态的关键组成部分。在目标1中 我们将阐明ATRX损失促进Alt细胞的机制 重组和生长。在AIM 2中，我们将研究ATRX的损失如何导致 Alt的激活。在AIM 3中，我们将探讨以下假设 肿瘤中的粘蛋白亚基SA1促进持续的端粒凝聚力和类似Alt的凝聚力 端粒维护机制。了解重组如何介导 Alt Cancer中的端粒长度维护将提供有关基本机制的见解 重组以及为抗癌疗法提供靶标。