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

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-kappa B, which is activated by PARP1 upon replication stress. In parallel, inflammatory cytokine gene expression is induced through the NF-kappa B-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.

Automated summary

In human primary cells, a noncanonical cellular response specific to nonblocking replication stress is discovered. This response generates reactive oxygen species (ROS) and activates detoxification genes. ROS are produced by DUOX1/DUOX2 and controlled by NF-kappa B.