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Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress

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  • Jérémy Sandoz

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Max Cigrang

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Amélie Zachayus

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Philippe Catez

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Lise-Marie Donnio

    (Université Claude Bernard Lyon 1)

  • Clèmence Elly

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Jadwiga Nieminuszczy

    (The Institute of Cancer Research)

  • Pietro Berico

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Cathy Braun

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Sergey Alekseev

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Jean-Marc Egly

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Wojciech Niedzwiedz

    (The Institute of Cancer Research)

  • Giuseppina Giglia-Mari

    (Université Claude Bernard Lyon 1)

  • Emmanuel Compe

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

  • Frédéric Coin

    (C.U. Equipe Labellisée Ligue contre le Cancer
    Centre National de la Recherche Scientifique
    Institut National de la Santé et de la Recherche Médicale
    Université de Strasbourg)

Abstract

The transcriptional response to genotoxic stress involves gene expression arrest, followed by recovery of mRNA synthesis (RRS) after DNA repair. We find that the lack of the EXD2 nuclease impairs RRS and decreases cell survival after UV irradiation, without affecting DNA repair. Overexpression of wild-type, but not nuclease-dead EXD2, restores RRS and cell survival. We observe that UV irradiation triggers the relocation of EXD2 from mitochondria to the nucleus. There, EXD2 is recruited to chromatin where it transiently interacts with RNA Polymerase II (RNAPII) to promote the degradation of nascent mRNAs synthesized at the time of genotoxic attack. Reconstitution of the EXD2-RNAPII partnership on a transcribed DNA template in vitro shows that EXD2 primarily interacts with an elongation-blocked RNAPII and efficiently digests mRNA. Overall, our data highlight a crucial step in the transcriptional response to genotoxic attack in which EXD2 interacts with elongation-stalled RNAPII on chromatin to potentially degrade the associated nascent mRNA, allowing transcription restart after DNA repair.

Suggested Citation

  • Jérémy Sandoz & Max Cigrang & Amélie Zachayus & Philippe Catez & Lise-Marie Donnio & Clèmence Elly & Jadwiga Nieminuszczy & Pietro Berico & Cathy Braun & Sergey Alekseev & Jean-Marc Egly & Wojciech Ni, 2023. "Active mRNA degradation by EXD2 nuclease elicits recovery of transcription after genotoxic stress," Nature Communications, Nature, vol. 14(1), pages 1-13, December.
  • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-35922-5
    DOI: 10.1038/s41467-023-35922-5
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    References listed on IDEAS

    as
    1. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
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