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: 9323358
• 负责人: RACHEL L. FLYNN
• 金额: $ 37.63万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-08-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9323358
• 关键词: ATR gene; Actins; Binding; Binding Proteins; Cell Aging; Cell Death; Cell Survival; Cell division; Cells; Chromatin; Chromatin Remodeling Factor; Chromosome Fragile Sites; Chromosome Segregation; Chromosomes; Clinical Trials; DNA; DNA Damage; DNA Sequence Alteration; DNA annealing; DNA replication fork; Data; Death Domain; Defect; Dependence; Enzyme Reactivation; Event; Genetic Recombination; Genome; Genome Stability; Goals; Histones; Human; Human Genome; Lead; Maintenance; Malignant Neoplasms; Mammalian Cell; Mediating; Molecular; Molecular Chaperones; Nature; Nucleosomes; Pathway interactions; Phenotype; Phosphotransferases; Proteins; Regulation; Role; Site; Somatic Cell; Stress; Telomerase; Telomerase Inhibitor; Telomere Capping; Telomere Maintenance; Telomere Pathway; Telomere Shortening; Tissues; Treatment Efficacy; Variant; Xenograft procedure; alternative treatment; biological adaptation to stress; cancer cell; cancer therapy; chromatin remodeling; efficacy testing; helicase; homologous recombination; improved; in vivo; metaplastic cell transformation; mouse model; nondeletion type alpha-thalassemia/mental retardation syndrome; osteosarcoma; repaired; response; targeted cancer therapy; targeted treatment; telomere; treatment strategy; tumor growth; tumor progression

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.

端粒覆盖着线性染色体的末端，为人类提供了一个分子屏障。 基因组在每次细胞分裂后，端粒的逐渐缩短会侵蚀这一屏障，并威胁到细胞的生长。 基因组的稳定性。极短或功能失调的端粒诱导复制性衰老和/或细胞凋亡。 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短端粒相关。重新启动 端粒酶，或端粒替代延长（ALT）途径的激活，解释了 在大多数人类癌症中的细胞永生化。端粒延长机制是活跃的， 然而，在所有癌细胞中的大多数，它们在正常体细胞中不存在或无效，使它们成为理想的 靶向癌症治疗的候选人。目前，临床试验正在进行中，以测试 然而，对于癌症的治疗，没有依赖于端粒酶抑制剂的治疗。 端粒维持的ALT途径。这些努力在一定程度上受到不完整的 了解调节ALT途径的分子机制。最近，我们证明， 共济失调毛细血管扩张和Rad 3相关（ATR）DNA损伤反应激酶是ALT的关键调节因子， 通路ATR激酶活性的抑制不仅减少端粒重组，而且还导致 在ALT阳性癌细胞中显著和选择性致死。虽然这些研究首次证明了 ATR在维持ALT通路中的功能要求，确切地说ATR如何调节ALT活性 以及ATR是否可以在ALT癌症的背景下进行治疗靶向，仍然不清楚。因此，我们认为， 这项提案的目的是梳理ATR在ALT通路中的功能，验证治疗方案， ATR抑制在ALT阳性癌症中的疗效，并继续确定调节 ALT活性。