The activation of ATR during unperturbed DNA replication is restricted by VCP/p97 through the extraction of DNA polymerase α/Primase from chromatin

Abstract

The replication stress response is an essential pathway that deals with the lesions that halt the progression of DNA replication forks even during an unperturbed S phase. Basal activation of the ATR and CHK1 kinases prevents the premature firing of origins of replication during S phase, avoiding the activation of an excessive number of replication forks and the appearance of genomic instability. However, the mechanisms that regulate ATR activation in the unperturbed S phase have not been fully determined. Here we present evidence showing that the AAA ATPase VCP/p97 regulates the presence of the DNA polymerase α/Primase complex (POLA/PRIM) on chromatin after origin firing, thus limiting the generation of primed DNA structures that mediate the activation of ATR by TOPBP1. As a consequence, inhibiting VCP/p97 activates ATR and CHK1 leading to cell cycle arrest in G2/M. We propose that the loading of POLA/PRIM after origin firing drives the basal activation of ATR during an unperturbed S phase and VCP/p97 regulates this activation through the extraction of POLA/PRIM from chromatin.