A noncanonical response to replication stress protects genome stability through ROS production, in an adaptive manner

Sandrine Ragu, Nathalie Droin, Gabriel Matos-Rodrigues, Aurélia Barascu, Sylvain Caillat, Gabriella Zarkovic, Capucine Siberchicot, Elodie Dardillac, Camille Gelot, Josée Guirouilh-Barbat, J. Pablo Radicella, Alexander A. Ishchenko, Jean Luc Ravanat, Eric Solary, Bernard S. Lopez

    Résultats de recherche: Contribution à un journalArticleRevue par des pairs

    9 Citations (Scopus)

    Résumé

    Cells are inevitably challenged by low-level/endogenous stresses that do not arrest DNA replication. Here, in human primary cells, we discovered and characterized a noncanonical cellular response that is specific to nonblocking replication stress. Although this response generates reactive oxygen species (ROS), it induces a program that prevents the accumulation of premutagenic 8-oxoguanine in an adaptive way. Indeed, replication stress-induced ROS (RIR) activate FOXO1-controlled detoxification genes such as SEPP1, catalase, GPX1, and SOD2. Primary cells tightly control the production of RIR: They are excluded from the nucleus and are produced by the cellular NADPH oxidases DUOX1/DUOX2, whose expression is controlled by NF-κB, which is activated by PARP1 upon replication stress. In parallel, inflammatory cytokine gene expression is induced through the NF-κB-PARP1 axis upon nonblocking replication stress. Increasing replication stress intensity accumulates DNA double-strand breaks and triggers the suppression of RIR by p53 and ATM. These data underline the fine-tuning of the cellular response to stress that protects genome stability maintenance, showing that primary cells adapt their responses to replication stress severity.

    langue originaleAnglais
    Pages (de - à)1349-1365
    Nombre de pages17
    journalCell Death and Differentiation
    Volume30
    Numéro de publication5
    Les DOIs
    étatPublié - 1 mai 2023

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