Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.

Autor:	Biancon G; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA. Electronic address: giulia.biancon@yale.edu., Joshi P; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Zimmer JT; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT, USA., Hunck T; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Gao Y; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Lessard MD; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA., Courchaine E; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA., Barentine AES; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA., Machyna M; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA., Botti V; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA., Qin A; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Gbyli R; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Patel A; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA., Song Y; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA; Department of Hematologic Oncology, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China., Kiefer L; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA; Department of Neurology, University of California, San Francisco, San Francisco, CA, USA., Viero G; Institute of Biophysics, CNR, Trento, Italy., Neuenkirchen N; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA., Lin H; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA., Bewersdorf J; Department of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA., Simon MD; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA; Institute for Biomolecular Design and Discovery, Yale University, West Haven, CT, USA., Neugebauer KM; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA., Tebaldi T; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA; Department of Cellular, Computational and Integrative Biology (CIBIO), University of Trento, Trento, Italy. Electronic address: toma.tebaldi@unitn.it., Halene S; Section of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA; Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA; Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA; Department of Pathology, Yale University School of Medicine, New Haven, CT, USA. Electronic address: stephanie.halene@yale.edu.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2022 Mar 17; Vol. 82 (6), pp. 1107-1122.e7.
DOI:	10.1016/j.molcel.2022.02.025
Abstrakt:	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. Competing Interests: 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. (Copyright © 2022 Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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