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Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

Author

Listed:
  • David Rombaut

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Université Paris Cité
    Laboratory of Hematology)

  • Carine Lefèvre

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Université Paris Cité)

  • Tony Rached

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Sabrina Bondu

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Anne Letessier

    (Institut Cochin)

  • Raphael M. Mangione

    (Institut Jacques Monod)

  • Batoul Farhat

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Auriane Lesieur-Pasquier

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Daisy Castillo-Guzman

    (University of California)

  • Ismael Boussaid

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Laboratory of Hematology)

  • Chloé Friedrich

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Laboratory of Hematology)

  • Aurore Tourville

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Magali De Carvalho

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Françoise Levavasseur

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Marjorie Leduc

    (Institut Cochin
    Université Paris Cité, Institut Cochin)

  • Morgane Le Gall

    (Institut Cochin
    Université Paris Cité, Institut Cochin)

  • Sarah Battault

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale)

  • Marie Temple

    (Laboratory of Hematology)

  • Alexandre Houy

    (Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer)

  • Didier Bouscary

    (Institut Cochin
    Hôpital Cochin, Clinical Department of Hematology)

  • Lise Willems

    (Institut Cochin
    Hôpital Cochin, Clinical Department of Hematology)

  • Sophie Park

    (Centre Hospitalier Universitaire, Université de Grenoble Alpes)

  • Sophie Raynaud

    (Université Côte d’Azur, Centre Hospitalier Universitaire)

  • Thomas Cluzeau

    (Université Côte d’Azur, Centre Hospitalier Universitaire)

  • Emmanuelle Clappier

    (Laboratory of Hematology)

  • Pierre Fenaux

    (Service Hématologie Séniors)

  • Lionel Adès

    (Service Hématologie Séniors)

  • Raphael Margueron

    (Paris Sciences Lettres Research University, Sorbonne University, INSERM U934)

  • Michel Wassef

    (Paris Sciences Lettres Research University, Sorbonne University, INSERM U934)

  • Samar Alsafadi

    (Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer)

  • Nicolas Chapuis

    (Institut Cochin
    Laboratory of Hematology)

  • Olivier Kosmider

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Laboratory of Hematology)

  • Eric Solary

    (INSERM 1287, Université Paris Saclay)

  • Angelos Constantinou

    (Université de Montpellier)

  • Marc-Henri Stern

    (Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer)

  • Nathalie Droin

    (INSERM 1287, Université Paris Saclay)

  • Benoit Palancade

    (Institut Jacques Monod)

  • Benoit Miotto

    (Institut Cochin)

  • Frédéric Chédin

    (University of California)

  • Michaela Fontenay

    (Institut Cochin
    Equipe labellisée par la Fondation pour la Recherche Médicale
    Université Paris Cité
    Laboratory of Hematology)

Abstract

Myelodysplastic syndromes (MDS) with mutated SF3B1 gene present features including a favourable outcome distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we find that SF3B1-mutated MDS show reduced R-loop formation predominating in gene bodies associated with intron retention reduction, not found in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibit augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation. Importantly, histone deacetylase inhibition using vorinostat restores R-loop formation, slows down DNA replication forks and improves SF3B1-mutated erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress represents a hallmark of SF3B1-mutated MDS ineffective erythropoiesis, which could be used as a therapeutic target.

Suggested Citation

  • 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.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-46547-7
    DOI: 10.1038/s41467-024-46547-7
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    References listed on IDEAS

    as
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