학술논문
Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation
Document Type
article
Author
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
Source
Nature Communications, Vol 15, Iss 1, Pp 1-20 (2024)
Subject
Language
English
ISSN
2041-1723
Abstract
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.