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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

基本信息

批准号：
9175196
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
项目类别：
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/9175196
关键词：
ATR gene Accounting 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 DAXX gene 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 Histocompatibility Testing 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 Thalassemia Treatment Efficacy Variant X-Linked Mental Retardation 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 micronucleus mouse model osteosarcoma repaired response targeted cancer therapy telomere treatment strategy tumor growth tumor progression

项目摘要

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.

端粒位于线性染色体的末端，为人类提供了分子屏障