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Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner

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  • Julien N. Bianco

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer
    University of Cologne)

  • Valérie Bergoglio

    (University of Toulouse 3)

  • Yea-Lih Lin

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer)

  • Marie-Jeanne Pillaire

    (University of Toulouse 3)

  • Anne-Lyne Schmitz

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer)

  • Julia Gilhodes

    (Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O))

  • Amelie Lusque

    (Institute Universitaire du Cancer Toulouse-Oncopole (IUCT-O))

  • Julien Mazières

    (Toulouse University Hospital, University Paul Sabatier)

  • Magali Lacroix-Triki

    (Gustave Roussy Cancer Campus)

  • Theodoros I. Roumeliotis

    (The Institute of Cancer Research)

  • Jyoti Choudhary

    (The Institute of Cancer Research)

  • Jérôme Moreaux

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer)

  • Jean-Sébastien Hoffmann

    (University of Toulouse 3)

  • Hélène Tourrière

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer)

  • Philippe Pasero

    (CNRS, Université de Montpellier, Equipe Labellisée Ligue Contre le Cancer)

Abstract

Oncogene-induced replication stress (RS) promotes cancer development but also impedes tumor growth by activating anti-cancer barriers. To determine how cancer cells adapt to RS, we have monitored the expression of different components of the ATR-CHK1 pathway in primary tumor samples. We show that unlike upstream components of the pathway, the checkpoint mediators Claspin and Timeless are overexpressed in a coordinated manner. Remarkably, reducing the levels of Claspin and Timeless in HCT116 cells to pretumoral levels impeded fork progression without affecting checkpoint signaling. These data indicate that high level of Claspin and Timeless increase RS tolerance by protecting replication forks in cancer cells. Moreover, we report that primary fibroblasts adapt to oncogene-induced RS by spontaneously overexpressing Claspin and Timeless, independently of ATR signaling. Altogether, these data indicate that enhanced levels of Claspin and Timeless represent a gain of function that protects cancer cells from of oncogene-induced RS in a checkpoint-independent manner.

Suggested Citation

  • Julien N. Bianco & Valérie Bergoglio & Yea-Lih Lin & Marie-Jeanne Pillaire & Anne-Lyne Schmitz & Julia Gilhodes & Amelie Lusque & Julien Mazières & Magali Lacroix-Triki & Theodoros I. Roumeliotis & Jy, 2019. "Overexpression of Claspin and Timeless protects cancer cells from replication stress in a checkpoint-independent manner," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08886-8
    DOI: 10.1038/s41467-019-08886-8
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    Cited by:

    1. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    2. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    3. Hervé Técher & Diyavarshini Gopaul & Jonathan Heuzé & Nail Bouzalmad & Baptiste Leray & Audrey Vernet & Clément Mettling & Jérôme Moreaux & Philippe Pasero & Yea-Lih Lin, 2024. "MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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