Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.
AML
MDS
RNA
RNA binding
RNA granules
U2AF1
freCLIP
splicing
stress granules
stress response
Journal
Molecular cell
ISSN: 1097-4164
Titre abrégé: Mol Cell
Pays: United States
ID NLM: 9802571
Informations de publication
Date de publication:
17 03 2022
17 03 2022
Historique:
received:
29
06
2021
revised:
21
12
2021
accepted:
15
02
2022
entrez:
18
3
2022
pubmed:
19
3
2022
medline:
12
4
2022
Statut:
ppublish
Résumé
Splicing factor mutations are common among cancers, recently emerging as drivers of myeloid malignancies. U2AF1 carries hotspot mutations in its RNA-binding motifs; however, how they affect splicing and promote cancer remain unclear. The U2AF1/U2AF2 heterodimer is critical for 3' splice site (3'SS) definition. To specifically unmask changes in U2AF1 function in vivo, we developed a crosslinking and immunoprecipitation procedure that detects contacts between U2AF1 and the 3'SS AG at single-nucleotide resolution. Our data reveal that the U2AF1 S34F and Q157R mutants establish new 3'SS contacts at -3 and +1 nucleotides, respectively. These effects compromise U2AF2-RNA interactions, resulting predominantly in intron retention and exon exclusion. Integrating RNA binding, splicing, and turnover data, we predicted that U2AF1 mutations directly affect stress granule components, which was corroborated by single-cell RNA-seq. Remarkably, U2AF1-mutant cell lines and patient-derived MDS/AML blasts displayed a heightened stress granule response, pointing to a novel role for biomolecular condensates in adaptive oncogenic strategies.
Identifiants
pubmed: 35303483
pii: S1097-2765(22)00163-0
doi: 10.1016/j.molcel.2022.02.025
pmc: PMC8988922
mid: NIHMS1784466
pii:
doi:
Substances chimiques
RNA Splice Sites
0
RNA-Binding Proteins
0
Splicing Factor U2AF
0
U2AF1 protein, human
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1107-1122.e7Subventions
Organisme : NCI NIH HHS
ID : R01 CA222518
Pays : United States
Organisme : NCATS NIH HHS
ID : UL1 TR001863
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK106857
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM137117
Pays : United States
Organisme : NIGMS NIH HHS
ID : R01 GM112766
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA200147
Pays : United States
Organisme : NIH HHS
ID : S10 OD023651
Pays : United States
Organisme : NIDDK NIH HHS
ID : U24 DK126127
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK102792
Pays : United States
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests S.H., consultancy, Forma Therapeutics. M.D.S., inventor on a patent application related to nucleotide recoding. G.V., scientific advisor of IMMAGINA Biotechnology s.r.l.
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