A role for nuclear actin filaments at damaged telomeres

核肌动蛋白丝在受损端粒处的作用

• 批准号: 8058216
• 负责人: Brittany Jo Belin
• 金额: $ 4.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8058216
• 关键词: role; nuclear; actin; filaments; damaged

DESCRIPTION (provided by applicant): Actin is among the most well characterized proteins in eukaryotic organisms and is required for many cytosolic processes, including cell motility, intracellular transport and the structural integrity of the cell. Recent reports have suggested that actin also participates in a range of nuclear processes in numerous cell types, though the role of this nuclear pool of actin is largely unknown. Previous work on nuclear actin has been limited due to the difficulty associated with visualizing actin in intact somatic nuclei. I have recently developed novel reporters of both monomeric and filamentous pools of nuclear actin in live cells. Using these tools in collaboration with the Blackburn lab, we have made the exciting discovery that actin filaments colocalize with uncapped telomeres. To investigate the role of telomeric actin, I propose to determine the live cell dynamics of nuclear actin with respect to both capped and deprotected telomeres. I will also investigate whether the association is dependent on the DNA damage response, as well as factors responsible for recruitment and regulation of telomeric actin. PUBLIC HEALTH RELEVANCE: Decades of experimental research on telomere biology have provided a clear link between telomere function and aging. Disruption or loss of active telomerase has been shown to cause telomeres to shorten and trigger cellular senescence, both in vivo and in vitro (Yu et al. 1990, Harley et al. 1990). When active telomerase is introduced into cell cultures with low telomerase activity, telomeres lengthen and the cells can become immortalized (Bodnar et al. 1998, Counter et al. 1998). From these observations, the traditional view that emerged was that the loss of telomere "critical length" promotes senescence. However, more recent evidence suggests that rather than telomere length per se, it is the loss of protection ("uncapping") of the telomere that results from telomere shortening that limits cell proliferation (Blackburn 2000). The proposed research identifies nuclear actin as a novel factor present at uncapped telomeres, and investigates potential roles for telomeric actin in signaling to the machineries involved in cell cycle exit, apoptosis and genomic instability. This research will provide insight into the consequences of uncapped telomeres that are responsible for promoting cellular senescence.

描述（由申请人提供）：肌动蛋白是真核生物中最有特征的蛋白质之一，是许多胞质过程所必需的，包括细胞运动，细胞内转运和细胞的结构完整性。最近的报道表明，肌动蛋白还参与了多种细胞类型的一系列核过程，尽管这种肌动蛋白的核池在很大程度上尚不清楚。由于与完整体细胞核中可视化肌动蛋白相关的困难，因此对核肌动蛋白的先前工作受到限制。我最近开发了活细胞中核肌动蛋白的单体和丝状池的新记者。使用这些工具与Blackburn Lab合作，我们做出了令人兴奋的发现，使肌动蛋白丝与未盖端粒共定位。为了研究端粒肌动蛋白的作用，我建议确定核肌动蛋白的活细胞动力学相对于限制和脱落的远程蛋白质。我还将调查该关联是否取决于DNA损伤反应以及负责端粒肌动蛋白募集和调节的因素。 公共卫生相关性：关于端粒生物学的数十年实验研究，在端粒功能和衰老之间提供了明确的联系。活跃端粒酶的破坏或丧失已显示导致端粒缩短和触发细胞衰老，无论是体内和体外的（Yu等，1990； Harley等，1990）。当将活性端粒酶引入具有低端粒酶活性的细胞培养物中时，端粒会延长，并且细胞可能会永生化（Bodnar等，1998，Counter等，1998）。从这些观察结果中，传统观点的出现是端粒损失“临界长度”会促进衰老。然而，最近的证据表明，端粒缩短而不是端粒的长度本身而不是端粒长度本身，而不是端粒的保护损失（布莱克本2000）。拟议的研究将核肌动蛋白确定为存在于未覆盖的端粒处的新因素，并研究了端粒肌动蛋白在向涉及细胞周期出口，凋亡，凋亡和基因组不稳定性的机器发出信号中的潜在作用。这项研究将洞悉负责促进细胞衰老的未覆盖端粒的后果。