PXD038656

PXD038656 is an original dataset announced via ProteomeXchange.

Title	DNA Replication Stress Due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation
Description	Myelodysplastic syndromes (MDS) with mutated SF3B1 gene have many features including a favorable outcome that are distinct from MDS with mutations in other splicing factor genes SRSF2 or U2AF1. Molecular bases of these divergences are poorly understood. Here we show that SF3B1-mutated MDS are characterized by a dramatically reduced R-loop formation predominating in gene bodies, which tightly associates with reduced retention of introns specifically found in SF3B1-mutated, but not in U2AF1- or SRSF2-mutated MDS. Compared to erythroblasts from SRSF2- or U2AF1-mutated patients, SF3B1-mutated erythroblasts exhibited augmented DNA synthesis, accelerated replication forks, and single-stranded DNA exposure upon differentiation, which were recapitulated in murine Sf3b1K700E/+ proerythroblasts. Importantly, R-loop formation was restored by histone deacetylase inhibition using SAHA/vorinostat, which improved Sf3b1K700E/+ erythroblast differentiation. In conclusion, loss of R-loops with associated DNA replication stress is a hallmark of SF3B1- mutated MDS ineffective erythropoiesis, which could be used as a new therapeutic target.
HostingRepository	PRIDE
AnnounceDate	2024-05-29
AnnouncementXML	Submission_2024-05-29_02:24:07.385.xml
DigitalObjectIdentifier
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Unsupported dataset by repository
PrimarySubmitter	Marjorie Leduc
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	acetylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	LTQ Orbitrap Elite

Revision	Datetime	Status	ChangeLog Entry
0	2022-12-07 12:07:40	ID requested
⏵ 1	2024-05-29 02:24:07	announced

10.1038/S41467-024-46547-7;

submitter keyword: R-loops, SF3B1,myelodysplastic syndromes, replication

Michaela Fontenay
contact affiliation	1 Université Paris Cité, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Institut Cochin 2 Equipe labellisée par la Fondation pour la Recherche Médicale, Paris, France 3 Laboratoire d’excellence du Globule Rouge GR-Ex, Université Paris Cité, Paris, France 4 Assistance Publique-Hôpitaux de Paris.Centre-Université Paris Cité, Hôpital Cochin, Laboratory of Hematology, Paris, France
contact email	michaela.fontenay@inserm.fr
lab head
Marjorie Leduc
contact affiliation	Plateforme protéomique 3P5, Université de Paris, Institut Cochin, INSERM, CNRS,
contact email	marjorie.leduc@inserm.fr
dataset submitter

Dataset FTP location NOTE: Most web browsers have now discontinued native support for FTP access within the browser window. But you can usually install another FTP app (we recommend FileZilla) and configure your browser to launch the external application when you click on this FTP link. Or otherwise, launch an app that supports FTP (like FileZilla) and use this address: ftp://ftp.pride.ebi.ac.uk/pride/data/archive/2024/05/PXD038656

PRIDE project URI

• PRIDE
  1. PXD038656
     1. Label: PRIDE project
     2. Name: DNA Replication Stress Due to Loss of R-Loops in Myelodysplastic Syndromes with SF3B1 Mutation