2025/07/01 by Sara Rodríguez‐Acebes, Rodrigo Martín-Rufo, Alicia Gómez-Moya +9 · 1 voice · 3 citations
Biochemistry, Genetics and Molecular Biology · Medicine · #Biology #Cancer therapeutics and mechanisms #Cancer-related Molecular Pathways #Cell biology #Chromatin #DNA #DNA Repair Mechanisms #DNA damage #DNA polymerase #DNA replication #Gene #Genetics #Genome instability #Molecular biology #Polymerase #Polymerase chain reaction #Primase
paper · pdf · doi:10.1038/s41467-025-60077-w
published in Nature Communications 16(1), 5706 (Nature Portfolio)
openalex publication_date 2025/07/01 · openalex created_date 2025/10/10 · openalex updated_date 2026/08/01
The replication stress response is an essential pathway that deals with the obstacles 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 that the AAA ATPase VCP/p97 regulates the presence of the DNA polymerase α/Primase complex (POLA/PRIM) on chromatin, thus limiting its activity and hampering the subsequent activation of ATR by TOPBP1. As a consequence, inhibiting VCP/p97 activates ATR and CHK1 and leads to a cell cycle arrest in G2/M. We propose that the priming activity of POLA/PRIM in the lagging strand is one of the determinants of the basal activation of ATR during an unperturbed S phase and VCP/p97 limits this activation through the extraction of POLA/PRIM from chromatin.