DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication
- Sara Rodríguez-Acebes
- Rodrigo Martín-Rufo
- Alicia Gómez-Moya
- Scott B. Churcher
- Alejandro Fernández-Llorente
- Guillermo de la Vega-Barranco
- Alejandra Perona
- Pilar Oroz
- Elena Martín-Doncel
- Luis Ignacio Toledo
- Juan Méndez
- Emilio Lecona
2025-07-01
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.