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

Journal

Nature communications
ISSN: 2041-1723
Titre abrégé: Nat Commun
Pays: England
ID NLM: 101528555

Informations de publication

Date de publication:
08 Apr 2024
Historique:
received: 07 12 2022
accepted: 29 02 2024
medline: 9 4 2024
pubmed: 9 4 2024
entrez: 8 4 2024
Statut: epublish

Résumé

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.

Identifiants

DOI: 10.1038/s41467-024-46547-7 PMID: 38589367
pubmed: 38589367
doi: 10.1038/s41467-024-46547-7
pii: 10.1038/s41467-024-46547-7
doi:

Types de publication

Journal Article

Langues

eng

Sous-ensembles de citation

IM

Pagination

3016

Informations de copyright

© 2024. The Author(s).

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Auteurs

David Rombaut (D)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Laboratoire d'excellence du Globule Rouge GR-Ex, Université Paris Cité, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0001-8910-0945

Carine Lefèvre (C)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Laboratoire d'excellence du Globule Rouge GR-Ex, Université Paris Cité, Paris, France.
ORCID: 0000-0003-3590-2445

Tony Rached (T)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
ORCID: 0009-0001-1347-7479

Sabrina Bondu (S)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.

Anne Letessier (A)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
ORCID: 0000-0002-1894-4072

Raphael M Mangione (RM)

Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.
ORCID: 0000-0001-6180-1926

Batoul Farhat (B)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
ORCID: 0000-0001-9462-8840

Auriane Lesieur-Pasquier (A)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.

Daisy Castillo-Guzman (D)

Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, CA, USA.

Ismael Boussaid (I)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0002-1839-8411

Chloé Friedrich (C)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0002-8640-9776

Aurore Tourville (A)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
ORCID: 0009-0008-2755-8369

Magali De Carvalho (M)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.

Françoise Levavasseur (F)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
ORCID: 0000-0001-6775-4542

Marjorie Leduc (M)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Platform Proteom'IC, Université Paris Cité, Institut Cochin, Paris, France.
ORCID: 0000-0002-4049-3976

Morgane Le Gall (M)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Platform Proteom'IC, Université Paris Cité, Institut Cochin, Paris, France.
ORCID: 0000-0002-4935-7065

Sarah Battault (S)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.

Marie Temple (M)

Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0002-5247-8976

Alexandre Houy (A)

Institut Curie, PSL Research University, Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France.
ORCID: 0000-0001-6267-2353

Didier Bouscary (D)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Clinical Department of Hematology, Paris, France.

Lise Willems (L)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Clinical Department of Hematology, Paris, France.

Sophie Park (S)

Department of Hematology, Centre Hospitalier Universitaire, Université de Grenoble Alpes, Grenoble, France.
ORCID: 0000-0003-0514-5789

Sophie Raynaud (S)

Laboratory of Hematology, Université Côte d'Azur, Centre Hospitalier Universitaire, Nice, France.

Thomas Cluzeau (T)

Clinical Department of Hematology, Université Côte d'Azur, Centre Hospitalier Universitaire, Nice, France.
ORCID: 0000-0002-6745-1127

Emmanuelle Clappier (E)

Assistance Publique-Hôpitaux de Paris.Nord-Université Paris Cité, Saint-Louis Hospital, Laboratory of Hematology, Paris, France.

Pierre Fenaux (P)

Assistance Publique-Hôpitaux de Paris.Nord-Université Paris Cité, Saint-Louis Hospital, Service Hématologie Séniors, Paris, France.

Lionel Adès (L)

Assistance Publique-Hôpitaux de Paris.Nord-Université Paris Cité, Saint-Louis Hospital, Service Hématologie Séniors, Paris, France.
ORCID: 0000-0002-9020-8766

Raphael Margueron (R)

Institut Curie, Paris Sciences Lettres Research University, Sorbonne University, INSERM U934, UMR3215, Paris, France.
ORCID: 0000-0002-9093-7977

Michel Wassef (M)

Institut Curie, Paris Sciences Lettres Research University, Sorbonne University, INSERM U934, UMR3215, Paris, France.

Samar Alsafadi (S)

Institut Curie, PSL Research University, Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France.
ORCID: 0000-0002-0060-1346

Nicolas Chapuis (N)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0003-0601-3948

Olivier Kosmider (O)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France.
ORCID: 0000-0002-6021-4057

Eric Solary (E)

Institut Gustave Roussy, INSERM 1287, Université Paris Saclay, Villejuif, France.
ORCID: 0000-0002-8629-1341

Angelos Constantinou (A)

Institut de Génétique Humaine, Centre National de la Recherche Scientifique, Université de Montpellier, Montpellier, France.
ORCID: 0000-0002-2994-8140

Marc-Henri Stern (MH)

Institut Curie, PSL Research University, Sorbonne University, INSERM U830, DNA repair and uveal melanoma, Equipe labellisée par la Ligue Nationale contre le Cancer, Paris, France.
ORCID: 0000-0002-8100-2272

Nathalie Droin (N)

Institut Gustave Roussy, INSERM 1287, Université Paris Saclay, Villejuif, France.
ORCID: 0000-0002-6099-5324

Benoit Palancade (B)

Université Paris Cité, CNRS, Institut Jacques Monod, Paris, France.
ORCID: 0000-0002-3894-9735

Benoit Miotto (B)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France.
ORCID: 0000-0003-2857-2126

Frédéric Chédin (F)

Department of Molecular and Cellular Biology and Genome Center, University of California, Davis, CA, USA.
ORCID: 0000-0002-1306-5335

Michaela Fontenay (M)

Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin, Paris, France. michaela.fontenay@inserm.fr.
Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France. michaela.fontenay@inserm.fr.
Laboratoire d'excellence du Globule Rouge GR-Ex, Université Paris Cité, Paris, France. michaela.fontenay@inserm.fr.
Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France. michaela.fontenay@inserm.fr.
ORCID: 0000-0002-5492-6349

Classifications MeSH