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

David Rombaut; Carine Lefèvre; Tony Rached; Sabrina Bondu; Anne Letessier; Raphael M. Mangione; Batoul Farhat; Auriane Lesieur-Pasquier; Daisy Castillo-Guzman; Ismael Boussaid; Chloé Friedrich; Aurore Tourville; Magali De Carvalho; Françoise Levavasseur; Marjorie Leduc; Morgane Le Gall; Sarah Battault; Marie Temple; Alexandre Houy; Didier Bouscary; Lise Willems; Sophie Park; Sophie Raynaud; Thomas Cluzeau; Emmanuelle Clappier; Pierre Fenaux; Lionel Adès; Raphael Margueron; Michel Wassef; Samar Alsafadi; Nicolas Chapuis; Olivier Kosmider; Eric Solary; Angelos Constantinou; Marc Henri Stern; Nathalie Droin; Benoit Palancade; Benoit Miotto; Frédéric Chédin; Michaela Fontenay

doi:10.1038/s41467-024-46547-7

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

David Rombaut, Carine Lefèvre, Tony Rached, Sabrina Bondu, Anne Letessier, Raphael M. Mangione, Batoul Farhat, Auriane Lesieur-Pasquier, Daisy Castillo-Guzman, Ismael Boussaid, Chloé Friedrich, Aurore Tourville, Magali De Carvalho, Françoise Levavasseur, Marjorie Leduc, Morgane Le Gall, Sarah Battault, Marie Temple, Alexandre Houy, Didier BouscaryLise Willems, Sophie Park, Sophie Raynaud, Thomas Cluzeau, Emmanuelle Clappier, Pierre Fenaux, Lionel Adès, Raphael Margueron, Michel Wassef, Samar Alsafadi, Nicolas Chapuis, Olivier Kosmider, Eric Solary, Angelos Constantinou, Marc Henri Stern, Nathalie Droin, Benoit Palancade, Benoit Miotto, Frédéric Chédin, Michaela Fontenay

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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.

langue originale	Anglais
Numéro d'article	3016
journal	Nature Communications
Volume	15
Numéro de publication	1
Les DOIs	https://doi.org/10.1038/s41467-024-46547-7
état	Publié - 1 déc. 2024

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10.1038/s41467-024-46547-7

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Rombaut, D., Lefèvre, C., Rached, T., Bondu, S., Letessier, A., Mangione, R. M., Farhat, B., Lesieur-Pasquier, A., Castillo-Guzman, D., Boussaid, I., Friedrich, C., Tourville, A., De Carvalho, M., Levavasseur, F., Leduc, M., Le Gall, M., Battault, S., Temple, M., Houy, A., ... Fontenay, M. (2024). Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation. Nature Communications, 15(1), Article 3016. https://doi.org/10.1038/s41467-024-46547-7

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

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.",

author = "David Rombaut and Carine Lef{\`e}vre and Tony Rached and Sabrina Bondu and Anne Letessier and Mangione, {Raphael M.} and Batoul Farhat and Auriane Lesieur-Pasquier and Daisy Castillo-Guzman and Ismael Boussaid and Chlo{\'e} Friedrich and Aurore Tourville and {De Carvalho}, Magali and Fran{\c c}oise Levavasseur and Marjorie Leduc and {Le Gall}, Morgane and Sarah Battault and Marie Temple and Alexandre Houy and Didier Bouscary and Lise Willems and Sophie Park and Sophie Raynaud and Thomas Cluzeau and Emmanuelle Clappier and Pierre Fenaux and Lionel Ad{\`e}s and Raphael Margueron and Michel Wassef and Samar Alsafadi and Nicolas Chapuis and Olivier Kosmider and Eric Solary and Angelos Constantinou and Stern, {Marc Henri} and Nathalie Droin and Benoit Palancade and Benoit Miotto and Fr{\'e}d{\'e}ric Ch{\'e}din and Michaela Fontenay",

note = "Publisher Copyright: {\textcopyright} The Author(s) 2024.",

year = "2024",

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doi = "10.1038/s41467-024-46547-7",

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Rombaut, D, Lefèvre, C, Rached, T, Bondu, S, Letessier, A, Mangione, RM, Farhat, B, Lesieur-Pasquier, A, Castillo-Guzman, D, Boussaid, I, Friedrich, C, Tourville, A, De Carvalho, M, Levavasseur, F, Leduc, M, Le Gall, M, Battault, S, Temple, M, Houy, A, Bouscary, D, Willems, L, Park, S, Raynaud, S, Cluzeau, T, Clappier, E, Fenaux, P, Adès, L, Margueron, R, Wassef, M, Alsafadi, S, Chapuis, N, Kosmider, O, Solary, E, Constantinou, A, Stern, MH, Droin, N, Palancade, B, Miotto, B, Chédin, F & Fontenay, M 2024, 'Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation', Nature Communications, VOL. 15, Numéro 1, 3016. https://doi.org/10.1038/s41467-024-46547-7

TY - JOUR

T1 - Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation

AU - Rombaut, David

AU - Lefèvre, Carine

AU - Rached, Tony

AU - Bondu, Sabrina

AU - Letessier, Anne

AU - Mangione, Raphael M.

AU - Farhat, Batoul

AU - Lesieur-Pasquier, Auriane

AU - Castillo-Guzman, Daisy

AU - Boussaid, Ismael

AU - Friedrich, Chloé

AU - Tourville, Aurore

AU - De Carvalho, Magali

AU - Levavasseur, Françoise

AU - Leduc, Marjorie

AU - Le Gall, Morgane

AU - Battault, Sarah

AU - Temple, Marie

AU - Houy, Alexandre

AU - Bouscary, Didier

AU - Willems, Lise

AU - Park, Sophie

AU - Raynaud, Sophie

AU - Cluzeau, Thomas

AU - Clappier, Emmanuelle

AU - Fenaux, Pierre

AU - Adès, Lionel

AU - Margueron, Raphael

AU - Wassef, Michel

AU - Alsafadi, Samar

AU - Chapuis, Nicolas

AU - Kosmider, Olivier

AU - Solary, Eric

AU - Constantinou, Angelos

AU - Stern, Marc Henri

AU - Droin, Nathalie

AU - Palancade, Benoit

AU - Miotto, Benoit

AU - Chédin, Frédéric

AU - Fontenay, Michaela

PY - 2024/12/1

Y1 - 2024/12/1

N2 - 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.

AB - 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.

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U2 - 10.1038/s41467-024-46547-7

DO - 10.1038/s41467-024-46547-7

M3 - Article

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SN - 2041-1723

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