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Article Dans Une Revue Cell Death and Differentiation Année : 2023

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

Bernard Lopez

Résumé

Abstract 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.
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Dates et versions

hal-04260214 , version 1 (26-10-2023)

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Sandrine Ragu, Nathalie Droin, Gabriel Matos-Rodrigues, Aurélia Barascu, Sylvain Caillat, et al.. A noncanonical response to replication stress protects genome stability through ROS production, in an adaptive manner. Cell Death and Differentiation, 2023, 30 (5), pp.1349-1365. ⟨10.1038/s41418-023-01141-0⟩. ⟨hal-04260214⟩
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