Structural Biology of Tetrahymena Telomerase Interactions at Telomeres

四膜虫端粒酶在端粒相互作用的结构生物学

基本信息

批准号：
2016540
负责人：
Juli Feigon
金额：
$ 87万
依托单位：
University of California-Los Angeles
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2024-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=2016540&HistoricalAwards=false
关键词：
Structural Biology Tetrahymena Telomerase Interactions

项目摘要

Telomerase is a special enzyme composed of proteins and RNA that maintains the DNA at the very ends of our chromosomes, called telomeres. Telomerase is a highly regulated determinant of stem cell renewal, aging, and tumorigenesis. In this research project, the PI will investigate the structure and function of proteins that interact with telomerase and telomeres. The project will use telomerase and telomere binding proteins from the model organism Tetrahymena, a ciliated protozoan, which has previously led to basic discoveries. This project will provide essential training for graduate students and postdoctoral fellows in structural biology and biophysics and help them become the next generation of leaders in this multidisciplinary field. This project will also train women, minority, and economically disadvantaged high school, undergraduate, and graduate students to pursue careers in science. Telomerase is an RNA-protein complex (RNP) that extends the 3’ ends of linear chromosomes by repetitively synthesizing the short telomere repeat sequence (TTGGGG in ciliates) using an RNA template embedded in its telomerase RNA (TER) and its specialized telomerase reverse transcriptase (TERT). Telomerase activity at telomeres counteracts the loss of DNA that would otherwise occur during each round of replication. Telomerase is recruited to telomeres and activated by telomere end protection proteins, which otherwise serve to protect telomere ends from being detected as double strand breaks by the DNA damage response. This project will use NMR spectroscopy, X-ray crystallography, cryo electron microscopy (cryoEM), and biochemical methods to investigate the structures and interactions of Tetrahymena telomerase 741 and TEB with p50 and with telomere end-protection proteins, to elucidate their roles in telomeric DNA synthesis, regulation, and end protection. This project is supported by the Molecular Biophysics Cluster of the Molecular and Cellular Biosciences Division in the Directorate for Biological Sciences.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

端粒酶是一种特殊的酶，由蛋白质和RNA组成，在我们的染色体末端保持DNA，称为端粒。端粒酶是由干细胞更新，衰老和肿瘤发生的高度调节。在该研究项目中，PI将研究与端粒和端粒相互作用的蛋白质的结构和功能。该项目将使用端粒酶和端粒结合蛋白来自模型有机体四环烷，这是一种纤毛的原生动物，以前已导致基本发现。该项目将为研究生和生物物理学的研究生和博士后研究员提供必要的培训，并帮助他们成为这个多学科领域的下一代领导者。该项目还将培训妇女，少数民族和经济上的高中，本科生和研究生从事科学职业。端粒酶是一种RNA蛋白质络合物（RNP），通过重复合成短端粒重复序列（ciliates中的TTGGGG），使用嵌入在其端粒RNA（TER）RNA（TER）及其专用望远镜反向转录酶（Terters）的RNA模板（TTGGGGGGG）的3'端来扩展线性染色体的3端。端粒的端粒酶活性抵消了每轮复制期间将发生的DNA的损失。端粒酶被招募到端粒并被端粒端保护蛋白激活，否则该蛋白可以保护端粒末端免于被DNA损伤响应检测到双链断裂。 This project will use NMR spectroscopy, X-ray crystallography, cryo electron microscopy (cryoEM), and biochemical methods to investigate the structures and interactions of Tetrahymena telomerase 741 and TEB with p50 and with telomere end-protection proteins, to elucidate their roles in telemeric DNA synthesis, regulation, and end protection.该项目得到了生物科学局的分子和细胞生物科学划分的分子生物物理学簇的支持。该奖项反映了NSF的法定任务，并被认为是通过基金会的智力优点和更广泛的影响来评估来支持的。