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
  • 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. [email protected].
  • # 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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