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

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 Niedzwiedz, Giuseppina Giglia-Mari, Emmanuel Compe and Frédéric Coin ()
Additional contact information
Jérémy Sandoz: C.U. Equipe Labellisée Ligue contre le Cancer
Max Cigrang: C.U. Equipe Labellisée Ligue contre le Cancer
Amélie Zachayus: C.U. Equipe Labellisée Ligue contre le Cancer
Philippe Catez: C.U. Equipe Labellisée Ligue contre le Cancer
Lise-Marie Donnio: Université Claude Bernard Lyon 1
Clèmence Elly: C.U. Equipe Labellisée Ligue contre le Cancer
Jadwiga Nieminuszczy: The Institute of Cancer Research
Pietro Berico: C.U. Equipe Labellisée Ligue contre le Cancer
Cathy Braun: C.U. Equipe Labellisée Ligue contre le Cancer
Sergey Alekseev: C.U. Equipe Labellisée Ligue contre le Cancer
Jean-Marc Egly: C.U. Equipe Labellisée Ligue contre le Cancer
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
Frédéric Coin: C.U. Equipe Labellisée Ligue contre le Cancer

Nature Communications, 2023, vol. 14, issue 1, 1-13

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-35922-5

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