Regulation of telomere recombination in ALT cancer cells

项目摘要 人类肿瘤细胞的无限复制能力依赖于它们的能力， 抵消伴随细胞分裂的端粒DNA的逐渐丢失。八十- 百分之五的癌症是通过上调端粒酶来实现这一点的，端粒酶是一种增加 端粒重复到染色体末端。剩余的15%激活ALT（替代 端粒的延长），一种基于重组的机制。据观察，ALT 在很大一部分人类肿瘤中被激活，结合这一概念， 可能为抗端粒酶治疗提供了一种适应机制，表明它是一种 是抗癌战略的重要目标。最近的研究确定了染色质- 重塑因子ATRX作为蛋白质最常丢失的ALT，但如何这种损失 端粒重组的影响尚不清楚。我们的研究揭示了一种机制： ATRX抑制有丝分裂时姐妹端粒凝聚的消退。所得 持续的端粒内聚促进姐妹端粒之间的染色单体交换， 同时抑制非姐妹之间的不适当重组。我们假设 端粒的持续凝聚力是ALT细胞状态的关键组成部分。目标1 我们将阐明ATRX的缺失促进ALT细胞增殖的机制， 重组和生长。在目标2中，我们将研究ATRX的丢失如何导致 ALT激活。在目标3中，我们将探讨上调的假设， 肿瘤中的粘附素亚单位SA 1促进持久的端粒粘附和ALT样 端粒维持机制。了解重组如何介导 ALT癌症中端粒长度的维持将提供对基本机制的见解 以及提供抗癌治疗的靶点。

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.