Regulation of telomere recombination in ALT cancer cells

人类肿瘤细胞的无限复制能力取决于它们的能力 抵消伴随细胞分裂而来的端粒DNA的逐渐丢失。八十个- 5%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。其余15%激活ALT(替代 端粒延长)，这是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，再加上它的概念 可能为抗端粒酶治疗提供一种适应性机制，表明它是一种 是抗癌策略的重要靶点。最近的研究发现染色质- 重塑因子ATRX作为ALT中最常丢失的蛋白质，但这种丢失是如何 影响端粒重组尚不清楚。我们的研究揭示了一种机制：丧失 ATRX抑制有丝分裂时姐妹端粒凝聚力的分解。由此产生的 持续的端粒凝聚力促进姐妹端粒之间的染色单体交换， 而它抑制了非姐妹之间的不适当重组。我们假设 这种持久的端粒凝聚力是ALT细胞状态的关键组成部分。在目标1中 我们将阐明ATRX缺失促进ALT细胞的机制 重组和成长。在目标2中，我们将调查ATRX的丢失是如何导致 谷丙转氨酶的激活。在目标3中，我们将探索这样一种假设，即上调 肿瘤中的粘附素亚基SA1促进持续的端粒凝聚力和ALT样蛋白 端粒维持机制。了解重组如何发挥中介作用 ALT癌症中端粒长度的维持将为深入了解基本机制提供帮助 并为抗癌治疗提供靶点。

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.