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A role for RNA in sister chromatid cohesion at human telomeres

RNA 在人类端粒姐妹染色单体凝聚力中的作用

基本信息

批准号：
10630053
负责人：
SUSAN SMITH
金额：
$ 42.36万
依托单位：
NEW YORK UNIVERSITY SCHOOL OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-06-01 至 2025-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10630053
关键词：
Aging Binding Biological Assay Buffers CRISPR/Cas technology Cell Aging Cell Cycle Arrest Cells Centromere Cessation of life Complex Cytoplasm DNA DNA Damage Data Ensure Genomic Instability Growth Human Hybrids In Vitro Investigation Knock-out Maintenance Malignant Neoplasms Measures Mitosis Monitor Nuclear Nucleoplasm Pathway interactions Phase Phase Transition Poly(ADP-ribose) Polymerases Process Proteins Proteomics RNA RNA Stability RNA metabolism RNA-Binding Proteins Regulation Resolution Ribonucleases Role S phase Sister Sister Chromatid Structure TNKS gene Tankyrase Telomerase Telomere Shortening Testing Untranslated RNA aged arm cancer cell cell age cohesion daughter cell genome integrity insight live cell imaging novel premature preservation prevent recruit response scaffold senescence small hairpin RNA telomere telomere loss

项目摘要

Project Summary Telomeres, specialized structures comprised of TTAGGG repeats and the six-subunit shelterin complex, require distinct mechanisms for their protection, replication, and cohesion. Following replication in S phase, sister chromatids are held together (cohered) until mitosis when they are distributed to daughter cells. Resolution of cohesion between sister telomeres requires the poly(ADP-ribose) polymerase, tankyrase 1. Tankyrase localizes to telomeres by binding to the TTAGGG-repeat binding shelterin subunit TRF1, in late S/G2 to resolve cohesion. In tankyrase 1 depleted cells sister telomeres remain cohered in mitosis (termed persistent telomere cohesion), despite normal resolution of sister chromatid arms and centromeres. This proposal builds on our recent discovery that persistent telomere cohesion serves a protective function (in the absence of telomerase) at critically short telomeres. We found that reduction of TRF1 (and the consequent tankyrase deficiency) at shortened telomeres in aged cells (or telomeres negative cancer cells) prevents resolution of cohesion and that this (unexpectedly) serves a protective role to prevent premature senescence or growth arrest. We will elucidate the mechanisms, which we show are RNA-based. Our identification of RNA-binding proteins as a significant group of tankyrase interactors in a proteomic screen prompted an investigation into a function for RNA in cohesion. Indeed, we have uncovered a role for the long non-coding telomere repeat-containing RNA (TERRA) in persistent telomere cohesion. We show that accumulation of TERRA and TERRA R-loops (RNA/DNA hybrids) occurs concomitant with persistent telomere cohesion to protect critically shortened telomeres. We will elucidate the proteins and pathways required to reduce TERRA levels for resolution of telomere cohesion, determine their role in ensuring protection of short telomeres in presenescent cells, and explore a potential phase transition mechanism used by tankyrase to resolve telomere cohesion. Our study provides a unifying and novel mechanism that relies on RNA, R-loops, and persistent telomere cohesion to buffer shortened telomeres and promote genome integrity.

项目总结