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Somatic genetic rescue of a germline ribosome assembly defect

Author

Listed:
  • Shengjiang Tan

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Laëtitia Kermasson

    (Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, INSERM UMR 1163)

  • Christine Hilcenko

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Vasileios Kargas

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • David Traynor

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Ahmed Z. Boukerrou

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Norberto Escudero-Urquijo

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Alexandre Faille

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Alexis Bertrand

    (Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, INSERM UMR 1163)

  • Maxim Rossmann

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Beatriz Goyenechea

    (Cambridge Biomedical Campus
    PolyProx Therapeutics, Babraham Research Campus)

  • Li Jin

    (Cambridge Biomedical Campus
    MRC Laboratory of Molecular Biology, Francis Crick Avenue, Cambridge Biomedical Campus)

  • Jonathan Moreil

    (Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, INSERM UMR 1163)

  • Olivier Alibeu

    (INSERM Unité Mixte de Recherche 1163, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Genomic Core Facility, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Blandine Beaupain

    (Assistance Publique-Hôpitaux de Paris, Trousseau Hospital)

  • Christine Bôle-Feysot

    (INSERM Unité Mixte de Recherche 1163, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Genomic Core Facility, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Stefano Fumagalli

    (Institut Necker Enfants Malades
    INSERM, U1151, Université Paris Descartes Sorbonne Cité)

  • Sophie Kaltenbach

    (Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité
    Service de cytogénétique, Hôpital Necker, Assistance Publique-Hôpitaux de Paris)

  • Jean-Alain Martignoles

    (Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Hématologie Biologique)

  • Cécile Masson

    (INSERM Unité Mixte de Recherche 1163, Bioinformatics Platform, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Patrick Nitschké

    (INSERM Unité Mixte de Recherche 1163, Bioinformatics Platform, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Mélanie Parisot

    (INSERM Unité Mixte de Recherche 1163, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Genomic Core Facility, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Aurore Pouliet

    (INSERM Unité Mixte de Recherche 1163, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Genomic Core Facility, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Isabelle Radford-Weiss

    (Université Paris Descartes, Faculté de Médecine Sorbonne Paris Cité
    Service de cytogénétique, Hôpital Necker, Assistance Publique-Hôpitaux de Paris)

  • Frédéric Tores

    (INSERM Unité Mixte de Recherche 1163, Bioinformatics Platform, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Jean-Pierre Villartay

    (Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, INSERM UMR 1163)

  • Mohammed Zarhrate

    (INSERM Unité Mixte de Recherche 1163, Structure Fédérative de Recherche Necker INSERM US24/CNRS UMS3633, Genomic Core Facility, Paris Descartes-Sorbonne Paris Cité University, Imagine Institute)

  • Ai Ling Koh

    (KK Women’s and Children’s Hospital
    SingHealth Duke-NUS Genomic Medicine Centre)

  • Kong Boo Phua

    (KK Women’s and Children’s Hospital
    SingHealth Duke-NUS Genomic Medicine Centre)

  • Bruno Reversade

    (Genome Institute of Singapore, A*STAR, Biopolis)

  • Peter J. Bond

    (Bioinformatics Institute (A*STAR)
    National University of Singapore)

  • Christine Bellanné-Chantelot

    (Sorbonne University)

  • Isabelle Callebaut

    (Sorbonne Université, Muséum National d’Histoire Naturelle, UMR CNRS 7590, Institut de Minéralogie, de Physique des Matériaux et de Cosmochimie, IMPMC)

  • François Delhommeau

    (Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine, AP-HP, Hôpital Saint-Antoine, Hématologie Biologique)

  • Jean Donadieu

    (Registre des neutropénies-Centre de référence des neutropénies chroniques)

  • Alan J. Warren

    (Cambridge Biomedical Campus Keith Peters Building, Hills Rd
    Cambridge Biomedical Campus
    Cambridge Biomedical Campus)

  • Patrick Revy

    (Université de Paris, Imagine Institute, Laboratory of Genome Dynamics in the Immune System, Equipe Labellisée Ligue contre le Cancer, INSERM UMR 1163)

Abstract

Indirect somatic genetic rescue (SGR) of a germline mutation is thought to be rare in inherited Mendelian disorders. Here, we establish that acquired mutations in the EIF6 gene are a frequent mechanism of SGR in Shwachman-Diamond syndrome (SDS), a leukemia predisposition disorder caused by a germline defect in ribosome assembly. Biallelic mutations in the SBDS or EFL1 genes in SDS impair release of the anti-association factor eIF6 from the 60S ribosomal subunit, a key step in the translational activation of ribosomes. Here, we identify diverse mosaic somatic genetic events (point mutations, interstitial deletion, reciprocal chromosomal translocation) in SDS hematopoietic cells that reduce eIF6 expression or disrupt its interaction with the 60S subunit, thereby conferring a selective advantage over non-modified cells. SDS-related somatic EIF6 missense mutations that reduce eIF6 dosage or eIF6 binding to the 60S subunit suppress the defects in ribosome assembly and protein synthesis across multiple SBDS-deficient species including yeast, Dictyostelium and Drosophila. Our data suggest that SGR is a universal phenomenon that may influence the clinical evolution of diverse Mendelian disorders and support eIF6 suppressor mimics as a therapeutic strategy in SDS.

Suggested Citation

  • Shengjiang Tan & Laëtitia Kermasson & Christine Hilcenko & Vasileios Kargas & David Traynor & Ahmed Z. Boukerrou & Norberto Escudero-Urquijo & Alexandre Faille & Alexis Bertrand & Maxim Rossmann & Bea, 2021. "Somatic genetic rescue of a germline ribosome assembly defect," Nature Communications, Nature, vol. 12(1), pages 1-17, December.
    • Handle: RePEc:nat:natcom:v:12:y:2021:i:1:d:10.1038_s41467-021-24999-5
    DOI: 10.1038/s41467-021-24999-5
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    Citations

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    Cited by:

    1. Sophie Tagnères & Paulo Espirito Santo & Julie Radermecker & Dana Rinaldi & Carine Froment & Quentin Provost & Manon Bongers & Solemne Capeille & Nick Watkins & Julien Marcoux & Pierre-Emmanuel Gleize, 2024. "SURF2 is a MDM2 antagonist in triggering the nucleolar stress response," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    2. Pekka Jaako & Alexandre Faille & Shengjiang Tan & Chi C. Wong & Norberto Escudero-Urquijo & Pablo Castro-Hartmann & Penny Wright & Christine Hilcenko & David J. Adams & Alan J. Warren, 2022. "eIF6 rebinding dynamically couples ribosome maturation and translation," Nature Communications, Nature, vol. 13(1), pages 1-11, December.
    3. Heather E. Machado & Nina F. Øbro & Nicholas Williams & Shengjiang Tan & Ahmed Z. Boukerrou & Megan Davies & Miriam Belmonte & Emily Mitchell & E. Joanna Baxter & Nicole Mende & Anna Clay & Philip Anc, 2023. "Convergent somatic evolution commences in utero in a germline ribosomopathy," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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