Molecular Mechanisms Regulating the Alternative Lengthening of Telomeres Pathway

调节端粒途径选择性延长的分子机制

• 批准号: 10630558
• 负责人: RACHEL L. FLYNN
• 金额: $ 4.99万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10630558
• 关键词: ATR gene; Cell Aging; Cell Death; Cell division; Chromosomes; Clinical Trials; DNA Damage; Enzyme Reactivation; Genetic Recombination; Genome Stability; Goals; Human; Human Genome; Lead; Maintenance; Malignant Neoplasms; Molecular; Pathway interactions; Phosphotransferases; Somatic Cell; Telomerase; Telomerase Inhibitor; Telomere Capping; Telomere Maintenance; Telomere Pathway; Telomere Shortening; Treatment Efficacy; cancer cell; cancer therapy; efficacy testing; metaplastic cell transformation; response; targeted cancer therapy; targeted treatment; telomere; tumor progression

PROJECT SUMMARY/ABSTRACT 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.

项目摘要/摘要 端粒覆盖了线性染色体的末端，为人类基因组提供了分子屏障。 在每次细胞分裂后，进行性的端粒缩短会侵蚀这一屏障，并威胁到细胞的稳定性 基因组。端粒过短或功能失调会导致复制性衰老和/或细胞死亡 最终会导致细胞衰老。然而，癌细胞克服了与以下因素相关的复制衰老 利用端粒延长机制使端粒变短。酶的重新激活 端粒酶，或端粒替代延长(ALT)途径的激活，占细胞 在大多数人类癌症中永生。端粒延长机制在大多数情况下是活跃的。 然而，在所有癌细胞中，它们在正常体细胞中不存在或无效，这使它们成为理想的候选细胞。 用于有针对性的癌症治疗。目前，正在进行临床试验以测试端粒酶抑制剂的疗效。 然而，在癌症的治疗中，没有依赖于ALT途径的癌症治疗方法 端粒维持。这些努力在一定程度上受到了对分子的不完全理解的限制 调节ALT途径的机制。最近，我们证实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途径的关键调节因子。对ATR的抑制 激酶活性不仅减少了端粒重组，而且还导致了显著和选择性的致死性。 ALT阳性癌细胞。虽然这些研究是第一次证明ATR在 维持ALT途径，ATR究竟如何调节ALT活性，以及ATR是否可以作为靶点 在ALT癌症的治疗方面，仍不清楚。因此，这一提议的目的是为了戏弄 除了ATR在ALT途径中的作用外，验证ATR抑制ALT的治疗效果 阳性癌症，并继续定义调节ALT活性的分子机制。

项目成果

RB loss sensitizes cells to replication-associated DNA damage after PARP inhibition by trapping.

• DOI: 10.26508/lsa.202302067
• 发表时间: 2023-12
• 期刊: LIFE SCIENCE ALLIANCE
• 影响因子: 4.4
• 作者: Zamalloa, Luis Gregory;Pruitt, Margaret M.;Hermance, Nicole M.;Gali, Himabindu;Flynn, Rachel L.;Manning, Amity L.
• 通讯作者: Manning, Amity L.