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.

端粒酶是一种由蛋白质和 RNA 组成的特殊酶，可维持染色体末端的 DNA，称为端粒酶，它是干细胞更新、衰老和肿瘤发生的高度调控的决定因素。与端粒酶和端粒相互作用的蛋白质的结构和功能该项目将使用来自模型生物四膜虫的端粒酶和端粒结合蛋白。该项目将为结构生物学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。该项目还将培训女性和少数族裔。端粒酶是一种 RNA-蛋白质复合物 (RNP)，可通过重复合成短端粒来延长线性染色体的 3' 末端。重复序列（纤毛虫中的 TTGGGG）使用嵌入其端粒酶 RNA (TER) 中的 RNA 模板及其端粒上的端粒酶逆转录酶 (TERT) 来抵消每轮复制过程中发生的 DNA 丢失。被招募到端粒并被端粒末端保护蛋白激活，否则端粒末端保护蛋白可以保护端粒末端不被检测为 DNA 损伤造成的双链断裂该项目将使用核磁共振波谱、X 射线晶体学、冷冻电子显微镜 (cryoEM) 和生化方法来研究四膜虫端粒酶 741 和 TEB 与 p50 和端粒末端保护蛋白的结构和相互作用，以阐明它们的作用。该项目由分子生物物理学集群支持。该奖项反映了 NSF 的法定使命，并通过使用基金会的智力价值和更广泛的影响审查标准进行评估，被认为值得支持。