IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60077-w.html
   My bibliography  Save this article

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

Author

Listed:
  • 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)

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.

Suggested Citation

  • 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 & Lui, 2025. "DNA polymerase α/primase extraction from chromatin by VCP/p97 restricts ATR activation during unperturbed DNA replication," Nature Communications, Nature, vol. 16(1), pages 1-16, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60077-w
    DOI: 10.1038/s41467-025-60077-w
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60077-w
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60077-w?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Chun Li & Shuchen Fan & Pan Li & Yuzhen Bai & Ye Wang & Yueyun Cui & Mengdi Li & Ruru Wang & Yuan Shao & Yingying Wang & Shuo Zheng & Rong Wang & Lijun Gao & Miaomiao Li & Yuanyuan Zheng & Fengting Wa, 2024. "A sophisticated mechanism governs Pol ζ activity in response to replication stress," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    2. Arthur J. Zaug & Karen J. Goodrich & Jessica J. Song & Ashley E. Sullivan & Thomas R. Cech, 2022. "Reconstitution of a telomeric replicon organized by CST," Nature, Nature, vol. 608(7924), pages 819-825, August.
    3. Qixiang He & Xiuhua Lin & Bianca L. Chavez & Sourav Agrawal & Benjamin L. Lusk & Ci Ji Lim, 2022. "Structures of the human CST-Polα–primase complex bound to telomere templates," Nature, Nature, vol. 608(7924), pages 826-832, August.
    4. Aline C. Simon & Jin C. Zhou & Rajika L. Perera & Frederick van Deursen & Cecile Evrin & Marina E. Ivanova & Mairi L. Kilkenny & Ludovic Renault & Svend Kjaer & Dijana Matak-Vinković & Karim Labib & A, 2014. "A Ctf4 trimer couples the CMG helicase to DNA polymerase α in the eukaryotic replisome," Nature, Nature, vol. 510(7504), pages 293-297, June.
    5. Zuzana Machacova & Katarina Chroma & David Lukac & Iva Protivankova & Pavel Moudry, 2024. "DNA polymerase α-primase facilitates PARP inhibitor-induced fork acceleration and protects BRCA1-deficient cells against ssDNA gaps," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    6. Jong-Bong Lee & Richard K. Hite & Samir M. Hamdan & X. Sunney Xie & Charles C. Richardson & Antoine M. van Oijen, 2006. "DNA primase acts as a molecular brake in DNA replication," Nature, Nature, vol. 439(7076), pages 621-624, February.
    7. Zuanning Yuan & Roxana Georgescu & Huilin Li & Michael E. O’Donnell, 2023. "Molecular choreography of primer synthesis by the eukaryotic Pol α-primase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    8. Zdenek Skrott & Martin Mistrik & Klaus Kaae Andersen & Søren Friis & Dusana Majera & Jan Gursky & Tomas Ozdian & Jirina Bartkova & Zsofia Turi & Pavel Moudry & Marianne Kraus & Martina Michalova & Jan, 2017. "Alcohol-abuse drug disulfiram targets cancer via p97 segregase adaptor NPL4," Nature, Nature, vol. 552(7684), pages 194-199, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Chiara Masnovo & Zohar Paleiov & Daniel Dovrat & Laurel K. Baxter & Sofia Movafaghi & Amir Aharoni & Sergei M. Mirkin, 2024. "Stabilization of expandable DNA repeats by the replication factor Mcm10 promotes cell viability," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    2. Clément Madru & Markel Martínez-Carranza & Sébastien Laurent & Alessandra C. Alberti & Maelenn Chevreuil & Bertrand Raynal & Ahmed Haouz & Rémy A. Meur & Marc Delarue & Ghislaine Henneke & Didier Flam, 2023. "DNA-binding mechanism and evolution of replication protein A," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    3. Zuanning Yuan & Roxana Georgescu & Huilin Li & Michael E. O’Donnell, 2023. "Molecular choreography of primer synthesis by the eukaryotic Pol α-primase," Nature Communications, Nature, vol. 14(1), pages 1-14, December.
    4. Maria Körner & Paul Müller & Hirak Das & Felix Kraus & Timo Pfeuffer & Sven Spielhaupter & Silke Oeljeklaus & Christina Schülein-Völk & J. Wade Harper & Bettina Warscheid & Alexander Buchberger, 2025. "p97/VCP is required for piecemeal autophagy of aggresomes," Nature Communications, Nature, vol. 16(1), pages 1-20, December.
    5. Weifeng Zhang & Zhuo Yang & Wenjie Wang & Qianwen Sun, 2024. "Primase promotes the competition between transcription and replication on the same template strand resulting in DNA damage," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    6. Yuanyuan Lei & Li Tang & Qiao Chen & Lingyi Wu & Wei He & Dianji Tu & Sumin Wang & Yuyang Chen & Shuang Liu & Zhuo Xie & Hong Wei & Shiming Yang & Bo Tang, 2022. "Disulfiram ameliorates nonalcoholic steatohepatitis by modulating the gut microbiota and bile acid metabolism," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    7. Markel Martínez-Carranza & Léa Vialle & Clément Madru & Florence Cordier & Ayten Dizkirici Tekpinar & Ahmed Haouz & Pierre Legrand & Rémy A. Meur & Patrick England & Rémi Dulermo & J. Iñaki Guijarro &, 2024. "Communication between DNA polymerases and Replication Protein A within the archaeal replisome," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    8. Aoran Dong & Guangyan Wei & Zhou Liang & Yuqin Di & Yuhao Tang & Yunyan Ling & Shuping Li & Yong Chen & Yi Zhou & Xiongjun Wang & Zhenwei Peng, 2025. "Gasdermin D aggravates a mouse model of radiation-induced liver disease by promoting chemokine secretion and neutrophil recruitment," Nature Communications, Nature, vol. 16(1), pages 1-17, December.
    9. Rishi Kumar Jaiswal & Kai-Hang Lei & Megan Chastain & Yuan Wang & Olga Shiva & Shan Li & Zhongsheng You & Peter Chi & Weihang Chai, 2023. "CaMKK2 and CHK1 phosphorylate human STN1 in response to replication stress to protect stalled forks from aberrant resection," Nature Communications, Nature, vol. 14(1), pages 1-18, December.
    10. Kaitlyn M. Abe & Gan Li & Qixiang He & Timothy Grant & Ci Ji Lim, 2024. "Small LEA proteins mitigate air-water interface damage to fragile cryo-EM samples during plunge freezing," Nature Communications, Nature, vol. 15(1), pages 1-11, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60077-w. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.