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SAMHD1 acts at stalled replication forks to prevent interferon induction

Author

Listed:
  • Flavie Coquel

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

  • Maria-Joao Silva

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer
    Peter MacCallum Cancer Centre)

  • Hervé Técher

    (IFOM, The FIRC Institute of Molecular Oncology)

  • Karina Zadorozhny

    (Masaryk University)

  • Sushma Sharma

    (Umeå University)

  • Jadwiga Nieminuszczy

    (The Institute of Cancer Research)

  • Clément Mettling

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Domiciliation, Activation Immunitaire et Infection)

  • Elodie Dardillac

    (Université Paris Sud, CNRS, UMR 8200 and Institut de Cancérologie Gustave Roussy)

  • Antoine Barthe

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

  • Anne-Lyne Schmitz

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

  • Alexy Promonet

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

  • Alexandra Cribier

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire de Virologie Moléculaire)

  • Amélie Sarrazin

    (Université de Montpellier, CNRS)

  • Wojciech Niedzwiedz

    (The Institute of Cancer Research)

  • Bernard Lopez

    (Université Paris Sud, CNRS, UMR 8200 and Institut de Cancérologie Gustave Roussy)

  • Vincenzo Costanzo

    (IFOM, The FIRC Institute of Molecular Oncology)

  • Lumir Krejci

    (Masaryk University
    St Anne’s University Hospital)

  • Andrei Chabes

    (Umeå University)

  • Monsef Benkirane

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire de Virologie Moléculaire)

  • Yea-Lih Lin

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

  • Philippe Pasero

    (Institut de Génétique Humaine, CNRS, Université de Montpellier, Laboratoire Maintien de l’Intégrité du Génome au cours de la Réplication, Ligue Contre le Cancer)

Abstract

SAMHD1 was previously characterized as a dNTPase that protects cells from viral infections. Mutations in SAMHD1 are implicated in cancer development and in a severe congenital inflammatory disease known as Aicardi–Goutières syndrome. The mechanism by which SAMHD1 protects against cancer and chronic inflammation is unknown. Here we show that SAMHD1 promotes degradation of nascent DNA at stalled replication forks in human cell lines by stimulating the exonuclease activity of MRE11. This function activates the ATR–CHK1 checkpoint and allows the forks to restart replication. In SAMHD1-depleted cells, single-stranded DNA fragments are released from stalled forks and accumulate in the cytosol, where they activate the cGAS–STING pathway to induce expression of pro-inflammatory type I interferons. SAMHD1 is thus an important player in the replication stress response, which prevents chronic inflammation by limiting the release of single-stranded DNA from stalled replication forks.

Suggested Citation

  • Flavie Coquel & Maria-Joao Silva & Hervé Técher & Karina Zadorozhny & Sushma Sharma & Jadwiga Nieminuszczy & Clément Mettling & Elodie Dardillac & Antoine Barthe & Anne-Lyne Schmitz & Alexy Promonet &, 2018. "SAMHD1 acts at stalled replication forks to prevent interferon induction," Nature, Nature, vol. 557(7703), pages 57-61, May.
    • Handle: RePEc:nat:nature:v:557:y:2018:i:7703:d:10.1038_s41586-018-0050-1
    DOI: 10.1038/s41586-018-0050-1
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    Citations

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    Cited by:

    1. Priya Kapoor-Vazirani & Sandip K. Rath & Xu Liu & Zhen Shu & Nicole E. Bowen & Yitong Chen & Ramona Haji-Seyed-Javadi & Waaqo Daddacha & Elizabeth V. Minten & Diana Danelia & Daniela Farchi & Duc M. D, 2022. "SAMHD1 deacetylation by SIRT1 promotes DNA end resection by facilitating DNA binding at double-strand breaks," Nature Communications, Nature, vol. 13(1), pages 1-18, December.
    2. Zu Ye & Shengfeng Xu & Yin Shi & Xueqian Cheng & Yuan Zhang & Sunetra Roy & Sarita Namjoshi & Michael A. Longo & Todd M. Link & Katharina Schlacher & Guang Peng & Dihua Yu & Bin Wang & John A. Tainer , 2024. "GRB2 stabilizes RAD51 at reversed replication forks suppressing genomic instability and innate immunity against cancer," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Oliver J. Acton & Devon Sheppard & Simone Kunzelmann & Sarah J. Caswell & Andrea Nans & Ailidh J. O. Burgess & Geoff Kelly & Elizabeth R. Morris & Peter B. Rosenthal & Ian A. Taylor, 2024. "Platform-directed allostery and quaternary structure dynamics of SAMHD1 catalysis," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    4. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    5. Cuige Zhu & Mari Iwase & Ziqian Li & Faliang Wang & Annabel Quinet & Alessandro Vindigni & Jieya Shao, 2022. "Profilin-1 regulates DNA replication forks in a context-dependent fashion by interacting with SNF2H and BOD1L," Nature Communications, Nature, vol. 13(1), pages 1-19, December.

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