Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability.

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Ressource 1Download: Genes Dev.-2018-Coutelier-1499-513.pdf (9832.53 [Ko])
State: Public
Version: Final published version
Serval ID
serval:BIB_0F776B7C9AE4
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Adaptation to DNA damage checkpoint in senescent telomerase-negative cells promotes genome instability.
Journal
Genes & development
Author(s)
Coutelier H., Xu Z., Morisse M.C., Lhuillier-Akakpo M., Pelet S., Charvin G., Dubrana K., Teixeira M.T.
ISSN
1549-5477 (Electronic)
ISSN-L
0890-9369
Publication state
Published
Issued date
01/12/2018
Peer-reviewed
Oui
Volume
32
Number
23-24
Pages
1499-1513
Language
english
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Abstract
In cells lacking telomerase, telomeres gradually shorten during each cell division to reach a critically short length, permanently activate the DNA damage checkpoint, and trigger replicative senescence. The increase in genome instability that occurs as a consequence may contribute to the early steps of tumorigenesis. However, because of the low frequency of mutations and the heterogeneity of telomere-induced senescence, the timing and mechanisms of genome instability increase remain elusive. Here, to capture early mutation events during replicative senescence, we used a combined microfluidic-based approach and live-cell imaging in yeast. We analyzed DNA damage checkpoint activation in consecutive cell divisions of individual cell lineages in telomerase-negative yeast cells and observed that prolonged checkpoint arrests occurred frequently in telomerase-negative lineages. Cells relied on the adaptation to the DNA damage pathway to bypass the prolonged checkpoint arrests, allowing further cell divisions despite the presence of unrepaired DNA damage. We demonstrate that the adaptation pathway is a major contributor to the genome instability induced during replicative senescence. Therefore, adaptation plays a critical role in shaping the dynamics of genome instability during replicative senescence.
Keywords
Adaptation, Physiological/genetics, Cell Cycle Checkpoints/genetics, DNA Damage/genetics, DNA Repair, Genome, Fungal/genetics, Genomic Instability/genetics, Microfluidic Analytical Techniques, Mutation, Optical Imaging, Saccharomyces cerevisiae/enzymology, Saccharomyces cerevisiae/genetics, Telomerase/genetics, Cdc5, DNA damage checkpoint, adaptation, genomic instability, senescence, telomere
Pubmed
Web of science
Open Access
Yes
Create date
13/12/2018 13:05
Last modification date
20/08/2019 13:36
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