2. Academic Validation
  3. DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication

DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication

  • Nat Commun. 2025 Jul 1;16(1):5706. doi: 10.1038/s41467-025-60077-w.
Sara Rodríguez-Acebes # 1,  Rodrigo Martín-Rufo # 2,  Alicia Gómez-Moya 2,  Scott B Churcher 2,  Alejandro Fernández-Llorente 2,  Guillermo de la Vega-Barranco 2,  Alejandra Perona 2,  Pilar Oroz 2,  Elena Martín-Doncel 3,  Luis Ignacio Toledo 3,  Juan Méndez 1,  Emilio Lecona 4
Affiliations

Affiliations

  • 1 DNA Replication Group, Molecular Oncology Programme, Spanish National Cancer Research Centre (CNIO), Madrid, Spain.
  • 2 Chromatin, Cancer and the Ubiquitin System lab, Centro de Biología Molecular Severo Ochoa (CBM) CSIC-Universidad Autónoma de Madrid, Department of Genome Dynamics and Function, Madrid, Spain.
  • 3 Center for Chromosome Stability, Institute for Cellular and Molecular Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 4 Chromatin, Cancer and the Ubiquitin System lab, Centro de Biología Molecular Severo Ochoa (CBM) CSIC-Universidad Autónoma de Madrid, Department of Genome Dynamics and Function, Madrid, Spain. elecona@cbm.csic.es.
  • # Contributed equally.
PMID: 40593507 DOI: 10.1038/s41467-025-60077-w
Abstract

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.

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