Stepwise Activation of the ATR Signaling Pathway upon Increasing Replication Stress Impacts Fragile Site Integrity - Institut Curie Accéder directement au contenu
Article Dans Une Revue PLoS Genetics Année : 2013

Stepwise Activation of the ATR Signaling Pathway upon Increasing Replication Stress Impacts Fragile Site Integrity

Résumé

Breaks at common fragile sites (CFS) are a recognized source of genome instability in pre-neoplastic lesions, but how such checkpoint-proficient cells escape surveillance and continue cycling is unknown. Here we show, in lymphocytes and fibroblasts, that moderate replication stresses like those inducing breaks at CFSs trigger chromatin loading of sensors and mediators of the ATR pathway but fail to activate Chk1 or p53. Consistently, we found that cells depleted of ATR, but not of Chk1, accumulate single-stranded DNA upon Mre11-dependent resection of collapsed forks. Partial activation of the pathway under moderate stress thus takes steps against fork disassembly but tolerates S-phase progression and mitotic onset. We show that fork protection by ATR is crucial to CFS integrity, specifically in the cell type where a given site displays paucity in backup replication origins. Tolerance to mitotic entry with under-replicated CFSs therefore results in chromosome breaks, providing a pool of cells committed to further instability.

Domaines

Génétique
Fichier principal
Vignette du fichier
journal.pgen.1003643.PDF (1.9 Mo) Télécharger le fichier
Origine : Publication financée par une institution
Loading...

Dates et versions

hal-01612094 , version 1 (06-10-2017)

Identifiants

Citer

Stéphane Koundrioukoff, Sandra Carignon, Hervé Techer, Anne Letessier, Olivier Brison, et al.. Stepwise Activation of the ATR Signaling Pathway upon Increasing Replication Stress Impacts Fragile Site Integrity. PLoS Genetics, 2013, 9 (7), pp.e1003643. ⟨10.1371/journal.pgen.1003643⟩. ⟨hal-01612094⟩
123 Consultations
96 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More