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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
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    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. 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.

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