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
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/12
Y1 - 2024/12
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.
UR - http://www.scopus.com/inward/record.url?scp=85189799689&partnerID=8YFLogxK
U2 - 10.1038/s41467-024-46547-7
DO - 10.1038/s41467-024-46547-7
M3 - Article
C2 - 38589367
AN - SCOPUS:85189799689
SN - 2041-1723
VL - 15
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 3016
ER -