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Human RAP 1 specifically protects telomeres of senescent cells from DNA damage
- Source :
- EMBO Reports, EMBO Reports, EMBO Press, 2020, 21 (4), ⟨10.15252/embr.201949076⟩
- Publication Year :
- 2020
- Publisher :
- HAL CCSD, 2020.
-
Abstract
- 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.<br />Human RAP1 specifically protects critically short telomeres from DNA damage response activation and telomere fusions in replicative senescent fibroblasts and tumor cells upon telomerase inhibition.
- Subjects :
- DNA Replication
Telomerase
endocrine system
DNA damage
telomeres Subject Categories Autophagy & Cell Death
Telomere Capping
[SDV]Life Sciences [q-bio]
Telomere-Binding Proteins
Biology
Biochemistry
non-homologous end joining
03 medical and health sciences
replicative senescence
0302 clinical medicine
Report
Genetics
chromosome fusions
Animals
Humans
Molecular Biology
Cellular Senescence
Recombination & Repair
030304 developmental biology
0303 health sciences
RAP1
DNA replication
DNA Replication, Repair & Recombination
Telomere
telomeres
Cell biology
Non-homologous end joining
Transcription Factor AP-1
enzymes and coenzymes (carbohydrates)
non‐homologous end joining
Rap1
Autophagy & Cell Death
Homologous recombination
030217 neurology & neurosurgery
DNA Damage
HeLa Cells
Reports
Subjects
Details
- Language :
- English
- ISSN :
- 1469221X and 14693178
- Database :
- OpenAIRE
- Journal :
- EMBO Reports, EMBO Reports, EMBO Press, 2020, 21 (4), ⟨10.15252/embr.201949076⟩
- Accession number :
- edsair.doi.dedup.....3edd1baa5852ef7a5e5d873b966d59f5