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Human RAP1 specifically protects telomeres of senescent cells from DNA damage

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posted on 2020-03-10, 14:21 authored by Liudmyla Lototska, Jia-Xing Yue, Marie-Josephine Giraud-Panis, Zhou Songyang, Nicola J. Royle, Gianni Liti, Jing Ye, Eric Gilson, Aaron Mendez-Bermudez
Repressor/activator protein 1 (RAP1) is a highly evolutionarily conserved protein found at telomeres. Although yeast Rap1 is a key telomere capping protein preventing non‐homologous end joining (NHEJ) and consequently telomere fusions, its role at mammalian telomeres in vivo is still controversial. Here, we demonstrate that RAP1 is required to protect telomeres in replicative senescent human cells. Downregulation of RAP1 in these cells, but not in young or dividing pre‐senescent cells, leads to telomere uncapping and fusions. The anti‐fusion effect of RAP1 was further explored in a HeLa cell line where RAP1 expression was depleted through an inducible CRISPR/Cas9 strategy. Depletion of RAP1 in these cells gives rise to telomere fusions only when telomerase is inhibited. We further show that the fusions triggered by RAP1 loss are dependent upon DNA ligase IV. We conclude that human RAP1 is specifically involved in protecting critically short telomeres. This has important implications for the functions of telomeres in senescent cells.

History

Citation

EMBO Rep (2020) e49076

Author affiliation

Department of Genetics

Version

  • VoR (Version of Record)

Published in

EMBO Reports

Publisher

EMBO Press

issn

1469-221X

Acceptance date

2020-01-29

Copyright date

2020

Available date

2020-02-25

Publisher version

https://www.embopress.org/doi/10.15252/embr.201949076

Language

en

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