Metabolic regulation of genome stability: Cells respond to metabolic fluctuations by adjusting the speed of DNA replication as a safeguard for genome stability. Somyajit et al. elucidate the cellular mechanisms that align replication fork dynamics with metabolic pathways (see the Perspective by Gómez-González and Aguilera). The elevation of reactive oxygen species (ROS) levels under metabolic stress dissociates a replication accelerator from the replisome and leads to replication slowdown, thus preventing replication stress. Studying this genome surveillance mechanism in cancer cells with elevated ROS levels and increased replication adaptability may provide opportunities to specifically target tumors. Science , this issue p. 797 ; see also p. 722

It has been long assumed that normally leading strand synthesis must proceed coordinated with the lagging strand to prevent strand uncoupling and the pathological accumulation of single-stranded DNA (ssDNA) in the cell, a dogma recently challenged by in vitro studies in prokaryotes. Here, we report that human DNA polymerases can function independently at each strand in vivo and that the resulting strand uncoupling is supported physiologically by a cellular tolerance to ssDNA. Active forks rapidly accumulate ssDNA at the lagging strand when POLA1 is inhibited without triggering a stress response, despite ssDNA formation being considered a hallmark of replication stress. Acute POLA1 inhibition causes a lethal RPA exhaustion, but cells can duplicate their DNA with limited POLA1 activity and exacerbated strand uncoupling as long as RPA molecules suffice to protect the elevated ssDNA. Although robust, this uncoupled mode of DNA replication is also an in-built weakness that can be targeted for cancer treatment.