Dysregulation of the low-level replication stress response in transformed cell lines

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Abstract

The canonical DNA damage response (cDDR) maintains genome stability, involving DNA synthesis arrest. However, unchallenged cells proliferate when they are continually exposed to low-level/endogenous replication stress. We previously characterized a noncanonical response specific to nonblocking replication stress, i.e. low-level stress (LoL-DDR), in primary cells. Although LoL-DDR generates replication stress-induced ROS (RIR), it prevents the accumulation of premutagenic 8-oxo-guanine (8-oxoG). Primary cells control RIR production via NADPH oxidases. Increasing the severity of replication stress above a threshold triggers the cDDR, leading to cell cycle arrest and RIR suppression, resulting in a peak-shaped dose response for RIR production. Here, we show that the LoL-DDR is dysregulated in cancer cell lines, which exhibit the following differences compared with primary cells: 1- RIR are not detoxified under high-level stress, resulting in a continuous increase in the dose‒response curve of RIR production; 2- RIR are not produced by NADPH oxidases; 3- replication stress favors the accumulation of the premutagenic 8-oxoG. Moreover, using an in vitro breast cancer progression model, we show that LoL-DDR dysregulation occurs at an early stage of cancer progression. Since, conversely, ROS trigger replication stress this establishes a “vicious circle” replication-stress/ROS that continuously jeopardizes genome integrity that should fuel and amplify tumorigenesis.

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