A starvation-triggered AAA+ ATPase halts chromosome replication progression by disassembling the bacterial DNA sliding clamp

Abstract

Living cells should coordinate vital events such as DNA replication with the availability of nutrients. For example, when cells encounter starvation, to maintain genomic integrity they should harbour robust mechanisms to stop DNA replication. Mechanisms regulating the progression of DNA replication when bacterial cells encounter starvation remain largely unclear. Herein, we identify the role of IncA -a AAA+ ATPase homologous to the prokaryotic RarA and eukaryotic WRNIP1/Mgs1- in inhibiting the progression of chromosome replication in nutrient-starved stationary phase cells of Caulobacter crescentus. We show that the starvation-induced alarmone (p)ppGpp ensures the confinement of IncA production to the stationary phase cells. At the mechanistic level, IncA directly interacts with the {beta}-sliding clamp protein DnaN and disassembles DnaN from the replisome, thereby stalling the progression of DNA replication. Furthermore, we reveal the requirement of IncAs ATPase activity for disassembling DnaN. Remarkably, we demonstrate that the IncA homolog from E. coli is capable of inhibiting DNA replication in Caulobacter. We propose that IncA homologs serve a stress-dependent role in inhibiting DNA replication across diverse domains of life.