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Defining the role of TCAB1 and its phase separation in telomerase assembly.

定义 TCAB1 的作用及其在端粒酶组装中的相分离。

基本信息

批准号：
10474274
负责人：
Jens Christopher Schmidt
金额：
$ 30.66万
依托单位：
MICHIGAN STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10474274
关键词：
Address Affect Apoptosis Automobile Driving Biochemical Biological Cell Nucleolus Cell physiology Cells Charge Chromosomes Complex Critical Pathways DNA DNA Sequence Defect Development Disease Dyskeratosis Congenita Exclusion Goals Homeostasis Human Human Chromosomes Human body In Vitro Interdisciplinary Study Label Laboratories Lead Liquid substance Malignant Neoplasms Methods Modeling Molecular N-terminal Nuclear Nucleic Acids Organelles Patients Peptides Phase Physiological Premature aging syndrome Proliferating Property Proteins RNA Folding RNA-Binding Proteins RNA-Directed DNA Polymerase Regulation Ribonucleoproteins Role Telomerase Telomerase RNA Component Telomere Maintenance Telomere Shortening Testing Therapeutic Time Tissues WD Repeat Work base cancer cell cancer therapy chromosome replication driving force experimental study molecular imaging novel strategies premature recruit single molecule stem cell population stem cell proliferation stem cells targeted treatment telomere therapy development tool trafficking tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Telomeres, the ends of human chromosomes, shorten every time a cell divides. When telomeres become too short, human cells stop dividing or undergo programmed cell death. Telomerase adds telomeric DNA onto chromosome ends to counteract telomere shortening. In the human body telomerase is expressed in stem cells, allowing them to continuously proliferate throughout our lives. Defects in telomerase function lead to premature aging diseases such as Dyskeratosis Congenita, which are caused by the depletion of stem cell populations. In addition, telomerase is expressed in ~90% of tumors and allows cancer cells to proliferate indefinitely. It is therefore critical to develop targeted approaches to promote or interfere with telomerase activity to treat premature aging diseases and cancer, respectively. Telomerase is a complex ribonucleoprotein that contains the telomerase reverse transcriptase protein (TERT), the telomerase RNA (TR), and various co-factors including the telomerase cajal body protein 1 (TCAB1). TCAB1 is required for telomerase function in human cells but the mechanism underlying its contribution to telomere maintenance is controversial. Initially it was suggested that telomerase is properly assembled and fully active in the absence of TCAB1, leading to the model that TCAB1 is required for telomerase trafficking to telomeres. More recent observations suggest that TCAB1 is required for telomerase catalytic activity by promoting TR folding without affecting overall RNP assembly. Importantly, all previous studies clearly demonstrate that TR is enriched in nucleoli in cells lacking TCAB1. Our prior work has shown that TERT is specifically excluded from nucleoli. We therefore believe that in the absence of TCAB1, telomerase fails to assemble because TR is trapped in nucleoli and TERT is excluded from nucleoli. Both nucleoli and Cajal bodies are phase separated nuclear organelles. Phase separation is an emerging molecular phenomenon by which proteins and nucleic acids from liquid like droplets. In preliminary experiments we have shown that TCAB1 contains disordered regions that can undergo liquid-liquid phase separation. Our central hypothesis is that the specific phase separation properties of TCAB1 facilitate telomerase assembly by driving the exclusion of the telomerase RNA from nucleoli and promoting its interaction with Cajal bodies. To test this hypothesis, we will address the following specific aims, (1) Determine the role of TCAB1 in telomerase assembly, and (2) Define the phase separation properties of TCAB1 and dissect their contribution to telomerase assembly.

项目总结/文摘