Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway

端粒覆盖了线性染色体的末端，为人类提供了一种分子屏障 基因组。在每次细胞分裂后，渐进性端粒缩短会侵蚀这一屏障，并威胁到 基因组的稳定性。严重短小或功能失调的端粒可诱导复制衰老和/或细胞 死亡，并最终导致细胞衰老。然而，癌细胞克服了复制性衰老 通过利用端粒延长的机制与极短的端粒相关。重新激活 酶端粒酶，或激活的交替延长的端粒(ALT)途径，占 在大多数人类癌症中细胞永生化。端粒延长机制在骨髓瘤中是活跃的 然而，大多数癌细胞在正常体细胞中不存在或无效，这使它们成为理想的癌细胞。 靶向癌症疗法的候选对象。目前，临床试验正在进行中，以测试 端粒酶抑制剂在癌症治疗中的作用，然而，目前还没有依赖于端粒酶抑制剂的癌症治疗方法 端粒维持的ALT途径。这些努力在一定程度上受到了不完整的 了解调节ALT途径的分子机制。最近，我们演示了 共济失调毛细血管扩张和RAD3相关(ATR)DNA损伤反应激酶是ALT的关键调节因子 路径。ATR激酶活性的抑制不仅减少了端粒重组，还导致了 对ALT阳性癌细胞的显著和选择性致死性。虽然这些研究是第一次证明 ATR在维持ALT途径中的功能要求，ATR究竟是如何调节ALT活性的 在ALT癌症的背景下，ATR是否可以作为治疗的靶点仍不清楚。因此， 这项建议的目标是梳理ATR在ALT途径中的功能，验证治疗 抑制ATR对ALT阳性癌症的疗效，并继续确定调控的分子机制 谷丙转氨酶活性。

Telomeres cap the ends of linear chromosomes and provide a molecular barrier for the human genome. Following each cell division, progressive telomere shortening erodes that barrier and threatens the stability of the genome. Critically short, or dysfunctional telomeres induce replicative senescence and/or cell death and ultimately, lead to cellular aging. Cancer cells, however, overcome the replicative senescence associated with critically short telomeres by exploiting mechanisms of telomere elongation. Reactivation of the enzyme telomerase, or activation of the Alternative Lengthening of Telomeres (ALT) pathway, account for cellular immortalization in the majority of human cancers. Telomere lengthening mechanisms are active in the majority of all cancer cells, however, they are absent or ineffective, in normal somatic cells making them ideal candidates for targeted cancer therapies. Currently, clinical trials are underway to test the efficacy of telomerase inhibitors in the treatment of cancer, however, there are no treatments for cancers that rely on the ALT pathway for telomere maintenance. These efforts have been limited, in part, by an incomplete understanding of the molecular mechanisms regulating the ALT pathway. Recently, we demonstrated that the ataxia telangiectasia and Rad3-related (ATR) DNA damage response kinase was a critical regulator of the ALT pathway. Inhibition of ATR kinase activity not only decreased telomeric recombination, but also led to significant and selective lethality in ALT positive cancer cells. While these studies were the first to demonstrate a functional requirement for ATR in maintenance of the ALT pathway, exactly how ATR regulates ALT activity and whether ATR can be targeted therapeutically in the context of ALT cancers, remains unclear. Therefore, the goal of this proposal is to tease apart the function of ATR within the ALT pathway, validate the therapeutic efficacy of ATR inhibition in ALT positive cancers, and continue to define the molecular mechanisms regulating ALT activity.