IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v7y2016i1d10.1038_ncomms10660.html
   My bibliography  Save this article

A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells

Author

Listed:
  • Akshay K. Ahuja

    (Institute of Molecular Cancer Research, University of Zurich)

  • Karolina Jodkowska

    (DNA Replication Group, Molecular Oncology Programme, CNIO)

  • Federico Teloni

    (Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich)

  • Anna H. Bizard

    (Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Panum Institute)

  • Ralph Zellweger

    (Institute of Molecular Cancer Research, University of Zurich)

  • Raquel Herrador

    (Institute of Molecular Cancer Research, University of Zurich)

  • Sagrario Ortega

    (Transgenic Mice Core Unit, Biotechnology Programme, CNIO)

  • Ian D. Hickson

    (Center for Chromosome Stability and Center for Healthy Aging, University of Copenhagen, Panum Institute)

  • Matthias Altmeyer

    (Institute of Veterinary Biochemistry and Molecular Biology, University of Zurich)

  • Juan Mendez

    (DNA Replication Group, Molecular Oncology Programme, CNIO)

  • Massimo Lopes

    (Institute of Molecular Cancer Research, University of Zurich)

Abstract

Embryonic stem cells (ESCs) represent a transient biological state, where pluripotency is coupled with fast proliferation. ESCs display a constitutively active DNA damage response (DDR), but its molecular determinants have remained elusive. Here we show in cultured ESCs and mouse embryos that H2AX phosphorylation is dependent on Ataxia telangiectasia and Rad3 related (ATR) and is associated with chromatin loading of the ssDNA-binding proteins RPA and RAD51. Single-molecule analysis of replication intermediates reveals massive ssDNA gap accumulation, reduced fork speed and frequent fork reversal. All these marks of replication stress do not impair the mitotic process and are rapidly lost at differentiation onset. Delaying the G1/S transition in ESCs allows formation of 53BP1 nuclear bodies and suppresses ssDNA accumulation, fork slowing and reversal in the following S-phase. Genetic inactivation of fork slowing and reversal leads to chromosomal breakage in unperturbed ESCs. We propose that rapid cell cycle progression makes ESCs dependent on effective replication-coupled mechanisms to protect genome integrity.

Suggested Citation

  • Akshay K. Ahuja & Karolina Jodkowska & Federico Teloni & Anna H. Bizard & Ralph Zellweger & Raquel Herrador & Sagrario Ortega & Ian D. Hickson & Matthias Altmeyer & Juan Mendez & Massimo Lopes, 2016. "A short G1 phase imposes constitutive replication stress and fork remodelling in mouse embryonic stem cells," Nature Communications, Nature, vol. 7(1), pages 1-11, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10660
    DOI: 10.1038/ncomms10660
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/ncomms10660
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/ncomms10660?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
    ---><---

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Sébastien Durand & Marion Bruelle & Fleur Bourdelais & Bigitha Bennychen & Juliana Blin-Gonthier & Caroline Isaac & Aurélia Huyghe & Sylvie Martel & Antoine Seyve & Christophe Vanbelle & Annie Adrait , 2023. "RSL24D1 sustains steady-state ribosome biogenesis and pluripotency translational programs in embryonic stem cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    2. Anchel de Jaime-Soguero & Janina Hattemer & Anja Bufe & Alexander Haas & Jeroen Berg & Vincent Batenburg & Biswajit Das & Barbara Marco & Stefania Androulaki & Nicolas Böhly & Jonathan J. M. Landry & , 2024. "Developmental signals control chromosome segregation fidelity during pluripotency and neurogenesis by modulating replicative stress," Nature Communications, Nature, vol. 15(1), pages 1-22, December.
    3. Clara Lopes Novo & Emily V. Wong & Colin Hockings & Chetan Poudel & Eleanor Sheekey & Meike Wiese & Hanneke Okkenhaug & Simon J. Boulton & Srinjan Basu & Simon Walker & Gabriele S. Kaminski Schierle &, 2022. "Satellite repeat transcripts modulate heterochromatin condensates and safeguard chromosome stability in mouse embryonic stem cells," Nature Communications, Nature, vol. 13(1), pages 1-16, 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:7:y:2016:i:1:d:10.1038_ncomms10660. 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.

    We have no bibliographic references for this item. You can help adding them by using 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.