mTOR-regulated U2af1 tandem exon splicing specifies transcriptome features for translational control

Jae Woong Chang, Hsin Sung Yeh, Meeyeon Park, Luke Erber, Jiao Sun, Sze Cheng, Alexander M. Bui, Naima Ahmed Fahmi, Ryan Nasti, Rui Kuang, Yue Chen, Wei Zhang, Jeongsik Yong

Research output: Contribution to journalArticle

Abstract

U2 auxiliary factor 1 (U2AF1) functions in 3'-splice site selection during pre-mRNA processing. Alternative usage of duplicated tandem exons in U2AF1 produces two isoforms, U2AF1a and U2AF1b, but their functional differences are unappreciated due to their homology. Through integrative approaches of genome editing, customized-transcriptome profiling and crosslinking-mediated interactome analyses, we discovered that the expression of U2AF1 isoforms is controlled by mTOR and they exhibit a distinctive molecular profile for the splice site and protein interactomes. Mechanistic dissection of mutually exclusive alternative splicing events revealed that U2AF1 isoforms' inherent differential preferences of nucleotide sequences and their stoichiometry determine the 3'-splice site. Importantly, U2AF1a-driven transcriptomes feature alternative splicing events in the 5'-untranslated region (5'-UTR) that are favorable for translation. These findings unveil distinct roles of duplicated tandem exon-derived U2AF1 isoforms in the regulation of the transcriptome and suggest U2AF1a-driven 5'-UTR alternative splicing as a molecular mechanism of mTOR-regulated translational control.

Original languageEnglish (US)
Pages (from-to)10373-10387
Number of pages15
JournalNucleic acids research
Volume47
Issue number19
DOIs
StatePublished - Nov 4 2019

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PubMed: MeSH publication types

  • Journal Article
  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

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