TY - JOUR
T1 - A noncanonical response to replication stress protects genome stability through ROS production, in an adaptive manner
AU - Ragu, Sandrine
AU - Droin, Nathalie
AU - Matos-Rodrigues, Gabriel
AU - Barascu, Aurélia
AU - Caillat, Sylvain
AU - Zarkovic, Gabriella
AU - Siberchicot, Capucine
AU - Dardillac, Elodie
AU - Gelot, Camille
AU - Guirouilh-Barbat, Josée
AU - Radicella, J. Pablo
AU - Ishchenko, Alexander A.
AU - Ravanat, Jean Luc
AU - Solary, Eric
AU - Lopez, Bernard S.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/5/1
Y1 - 2023/5/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85149201641&partnerID=8YFLogxK
U2 - 10.1038/s41418-023-01141-0
DO - 10.1038/s41418-023-01141-0
M3 - Article
C2 - 36869180
AN - SCOPUS:85149201641
SN - 1350-9047
VL - 30
SP - 1349
EP - 1365
JO - Cell Death and Differentiation
JF - Cell Death and Differentiation
IS - 5
ER -