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 Vega-Barranco, Alejandra Perona, Pilar Oroz, Elena Martín-Doncel, Luis Ignacio Toledo, Juan Méndez and Emilio Lecona ()
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Sara Rodríguez-Acebes: Spanish National Cancer Research Centre (CNIO)
Rodrigo Martín-Rufo: Department of Genome Dynamics and Function
Alicia Gómez-Moya: Department of Genome Dynamics and Function
Scott B. Churcher: Department of Genome Dynamics and Function
Alejandro Fernández-Llorente: Department of Genome Dynamics and Function
Guillermo Vega-Barranco: Department of Genome Dynamics and Function
Alejandra Perona: Department of Genome Dynamics and Function
Pilar Oroz: Department of Genome Dynamics and Function
Elena Martín-Doncel: University of Copenhagen
Luis Ignacio Toledo: University of Copenhagen
Juan Méndez: Spanish National Cancer Research Centre (CNIO)
Emilio Lecona: Department of Genome Dynamics and Function

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60077-w

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