ArticleMolecular cell2022
Precision analysis of mutant U2AF1 activity reveals deployment of stress granules in myeloid malignancies.
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Article in Molecular cell, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 55 papers.
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55 citing papers in PubMed, 77 citations in OpenAlex.
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Authors and funding
23 authors at 5 institutions in 3 countries.
Giulia BianconSection 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.
Poorval JoshiSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Joshua T ZimmerDepartment 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.
Torben HunckSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Yimeng GaoSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Mark D LessardDepartment of Cell Biology, Yale University School of Medicine, New Haven, CT, USA.
Edward CourchaineDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA.
Andrew E S BarentineDepartment of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
Martin MachynaDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA.
Valentina BottiDepartment of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT, USA.
Ashley QinSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Rana GbyliSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Amisha PatelSection of Hematology, Department of Internal Medicine, Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
Yuanbin SongSection 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.
Lea KieferDepartment 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.
Gabriella VieroInstitute of Biophysics, CNR, Trento, Italy.
Nils NeuenkirchenDepartment 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.
Haifan LinDepartment 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.
Joerg BewersdorfDepartment of Cell Biology, Yale University School of Medicine, New Haven, CT, USA; Department of Biomedical Engineering, Yale University, New Haven, CT, USA.
Matthew D SimonDepartment 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.
Karla M NeugebauerDepartment 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.
Toma TebaldiSection 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.
Stephanie HaleneSection 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.
Yale Cancer Center · USYale University · USSun Yat-sen University · CNUniversity of California, San Francisco · USUniversity of Trento · IT
Funding
Yale Clinical and Translational Science Award (U Component)UL1TR001863 · NCATS · YALE UNIVERSITY · PI John H. Krystal, LUCILA OHNO-MACHADO · 2016 to 2026
$102.9MThe second phase of NIH Common Fund 4D Nucleome Network Organizational HubU01CA200147 · NCI · UNIVERSITY OF CALIFORNIA, SAN DIEGO · PI ZHONG, SHENG · 2015 to 2024
$22.0MYale Cooperative Hematology Specialized Core CenterU54DK106857 · NIDDK · YALE UNIVERSITY · PI JOHN HWA, Diane S Krause · 2015 to 2026
$9.7MProteomics CoreU54DK110858 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Anna E Beaudin, JAMES Eric COX · 2016 to 2026
$8.6MHematology Central Coordinating Center (HCCC) for the NIDDK Hematology Centers ProgramU24DK126127 · NIDDK · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · PI Anna E Beaudin, DEREK L STIREWALT · 2020 to 2026
$7.5MCross-regulation between transcription and pre-mRNA splicingR01GM112766 · NIGMS · YALE UNIVERSITY · PI Karla M Neugebauer · 2015 to 2026
$5.3MMechanisms of Leukemogenesis in AMKLR01CA222518 · NCI · YALE UNIVERSITY · PI HALENE, STEPHANIE, KRAUSE, DIANE S · 2020 to 2024
$3.0MRevealing the dynamics of RNA metabolism with nucleotide recoding chemistryR01GM137117 · NIGMS · YALE UNIVERSITY · PI Matthew David Simon · 2020 to 2026
$2.6MThe role of mutant splicing factor SRSF2 in MyelodysplasiaR01DK102792 · NIDDK · YALE UNIVERSITY · PI HALENE, STEPHANIE · 2016 to 2019
$1.5MHigh Resolution Tandem Mass Spectrometer to Meet Growing Demand for Proteomics at YaleS10OD023651 · OD · YALE UNIVERSITY · PI LAM, TUKIET T · 2018 to 2018
$572kNCATS NIH HHS UL1 TR001863NCI NIH HHS R01 CA222518NCI NIH HHS U01 CA200147NIDDK NIH HHS R01 DK102792NIDDK NIH HHS U24 DK126127NIDDK NIH HHS U54 DK106857NIDDK NIH HHS U54 DK110858NIGMS NIH HHS R01 GM112766NIGMS NIH HHS R01 GM137117NIH HHS S10 OD023651
Abstract
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.
Indexed as
Leukemia, Myeloid, AcuteMyelodysplastic SyndromesSplicing Factor U2AFStress GranulesHumansMutationRNA-Binding ProteinsRNA Splice SitesRNA SplicingRNA-Binding ProteinsRNA Splice SitesSplicing Factor U2AFU2AF1 protein, humanAMLfreCLIPMDSRNARNA bindingRNA granulessplicingstress granulesstress responseU2AF1
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