Control of Telomere Heterochromatin by TERRA

TERRA 对端粒异染色质的控制

• 批准号: 7986763
• 负责人: PAUL M LIEBERMAN
• 金额: $ 35.15万
• 依托单位: WISTAR INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7986763
• 关键词: Age; Aging; B-Lymphocytes; Binding; Biological Markers; Bypass; Cancerous; Cell Aging; Cell Cycle; Cell Proliferation; Cells; Cellular Stress; Chromatin; Chromatin Structure; Complex; DNA; DNA Damage; DNA Methylation; DNA Repair; DNA biosynthesis; Data; Evolution; Functional RNA; Functional disorder; Genetic; Genetic Recombination; Goals; Growth; Heterochromatin; Heterogeneous-Nuclear Ribonucleoproteins; Histone H3; Histones; Human; Length; Lesion; Malignant Neoplasms; Molecular; Normal Cell; Nucleoproteins; Oncogenes; Play; Premalignant; Proteins; RNA; Regulation; Role; Signal Pathway; Signal Transduction; Staging; Stress; Structure; Telomerase; Telomere Repeat Binding Factor; Telomere Shortening; Testing; biological adaptation to stress; cancer cell; carcinogenesis; cell transformation; heterochromatin-specific nonhistone chromosomal protein HP-1; in vitro activity; neoplastic cell; novel; origin recognition complex; prevent; public health relevance; response; senescence; telomere

DESCRIPTION (provided by applicant): Telomeres and telomerase play a critical role in cellular aging and human carcinogenesis. Telomere shortening, telomerase activation, and genetic instability are among the best-characterized changes observed in age-associated senescence and pre-malignant neoplastic cells. In normal cells, telomere attrition is one mechanism that controls proliferative capacity and replicative aging. In most cancer cells, elevated telomerase levels bypass these normal constraints on telomere-associated growth regulation. Telomerase activity is regulated not only by the expression of its protein-components (via growth stimulation and oncogene signaling), but also by its access to telomere DNA and dynamic changes in the nucleoprotein structures formed at telomeres. The telomere-repeat binding factors (TRFs) function to prevent DNA recombination and DNA damage responses at normal telomeres. One of the functions of TRFs and their associated factors (termed shelterins) is to establish a chromatin structure that limits DNA recombination and other forms of DNA damage, yet is sufficiently dynamic to allow telomerase access to critically short telomeres each cell cycle. Recently, a non-coding RNA containing telomere repeats (referred to as TERRA) has been identified as a structural component of the shelterin complex. We have found that TERRA binds to key components of the shelterin complex and that it promotes heterochromatin formation through interactions with heterochromatin protein 1 (HP1), histone K3 K9me3, and the Origin Recognition Complex (ORC). TERRA abundance correlates inversely with telomerase expression and TERRA RNA can inhibit telomerase activity in vitro. TERRA expression is also suppressed in most telomerase positive cancer cells. Our preliminary data indicates that TERRA expression is induced by inhibition of cellular proliferation. The precise function of TERRA and its potential role as a telomere and telomerase regulatory molecule are just beginning to be explored in detail. In this proposal, we plan to test the hypothesis that TERRA is a central regulatory molecule that coordinates telomere heterochromatin formation with telomere length and cellular proliferation. The long-term goal of this proposal is to determine how telomeric heterochromatin is deregulated in cellular aging and cancer. PUBLIC HEALTH RELEVANCE: Telomere dysfunction is an early biomarker for dysplastic and pre-cancerous lesions. Telomere shortening and loss of telomere signals are commonly observed in early stage carcinogenesis, but their cause and contribution to cancer cell evolution is not known. In this application, we investigate the novel role of telomere heterochromatin in maintaining telomere stability and how this may be deregulated in human cancer. We will examine telomere chromatin alterations during cellular ageing and after immortalization of primary B-lymphocytes. These studies will provide new information on our understanding of telomere chromatin structure and genetic stability during the early stages of cancer cell transformation and normal cell senescence.

描述（由申请人提供）：端粒和端粒酶在细胞衰老和人类致癌作用中起关键作用。端粒缩短，端粒酶激活和遗传不稳定性是年龄相关衰老和恶性肿瘤细胞中观察到的最佳特征变化之一。在正常细胞中，端粒损耗是控制增殖能力和复制衰老的一种机制。在大多数癌细胞中，升高的端粒酶水平绕过了与端粒相关生长调节的这些正常限制。端粒酶活性不仅受其蛋白质元件的表达（通过生长刺激和癌基因信号传导）来调节，而且还通过其访问端粒DNA的访问以及端粒形成的核蛋白结构的动态变化来调节。端粒重复结合因子（TRF）功能，以防止正常端粒处的DNA重组和DNA损伤反应。 TRF的功能之一及其相关因素（称为庇护素）是建立限制DNA重组和其他形式的DNA损伤的染色质结构，但具有足够的动态性，可以使端粒酶访问每个细胞周期的关键短端粒。最近，一个含有端粒重复序列的非编码RNA（称为Terra）已被确定为庇护素复合物的结构成分。我们发现Terra与庇护素复合物的关键成分结合，并通过与异染色质蛋白1（HP1），组蛋白K3 K9me3和Origin识别复合物（ORC）（ORC）相互作用来促进异染色质形成。 Terra丰度与端粒酶表达相反，而Terra RNA可以在体外抑制端粒酶活性。在大多数端粒酶阳性癌细胞中也抑制Terra表达。我们的初步数据表明，Terra表达是通过抑制细胞增殖引起的。 Terra的精确功能及其作为端粒和端粒酶调节分子的潜在作用才刚刚开始详细探讨。在此提案中，我们计划检验以下假设：Terra是一种中央调节分子，该分子将端粒异染色质形成与端粒长度和细胞增殖。该提案的长期目标是确定端粒异染色质在细胞衰老和癌症中如何消失。 公共卫生相关性：端粒功能障碍是发育不良和癌性病变的早期生物标志物。在早期癌变中通常观察到端粒缩短和端粒信号的丧失，但是它们对癌细胞进化的原因和贡献尚不清楚。在此应用中，我们研究了端粒异染色质在维持端粒稳定性方面的新作用，以及在人类癌症中如何解除端粒稳定性的作用。我们将在细胞衰老期间和原发性B淋巴细胞的永生化过程中检查端粒染色质的改变。这些研究将提供有关我们在癌细胞转化和正常细胞衰老的早期阶段对端粒染色质结构和遗传稳定性的理解的新信息。