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Precision analysis
of mutant U2AF1 activity reveals deployment of stress granules in myeloid
malignancies
Biancon G, Joshi P,
Zimmer JT, Hunck T, Gao Y, Lessard MD, Courchaine E, Barentine AES,
Machyna M, Botti V, Qin A, Gbyli R, Patel A, Song Y, Kiefer L, Viero G, Neuenkirchen
N, Lin
H, Bewersdorf J, Simon MD, Neugebauer KM, Tebaldi T#^, Halene S. Precision
analysis
of mutant U2AF1 activity reveals deployment of stress granules in myeloid
malignancies. Mol
Cell. 2022 Mar 17;82(6):1107-1122.e7. (#Co-corresponding authorship, ^Journal
cover)
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.
DOI:
https://doi.org/10.1016/j.molcel.2022.02.025