The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation

Murali Palangat, Dimitrios G. Anastasakis, Dennis Liang Fei, Katherine E. Lindblad, Robert Bradley, Christopher S. Hourigan, Markus Hafner, Daniel R. Larson

Research output: Contribution to journalArticlepeer-review

50 Scopus citations

Abstract

Somatic mutations in the genes encoding components of the spliceosome occur frequently in human neoplasms, including myeloid dysplasias and leukemias, and less often in solid tumors. One of the affected factors, U2AF1, is involved in splice site selection, and the most common change, S34F, alters a conserved nucleic acid-binding domain, recognition of the 3 splice site, and alternative splicing of many mRNAs. However, the role that this mutation plays in oncogenesis is still unknown. Here, we uncovered a noncanonical function of U2AF1, showing that it directly binds mature mRNA in the cytoplasm and negatively regulates mRNA translation. This splicing-independent role of U2AF1 is altered by the S34F mutation, and polysome profiling indicates that the mutation affects translation of hundreds of mRNA. One functional consequence is increased synthesis of the secreted chemokine interleukin 8, which contributes to metastasis, inflammation, and cancer progression in mice and humans.

Original languageEnglish
Pages (from-to)482-497
Number of pages16
JournalGenes and Development
Volume33
Issue number9-10
DOIs
StatePublished - 1 May 2019
Externally publishedYes

Keywords

  • IL8
  • Myeloid leukemia
  • Splicing factor mutations
  • Translation regulator
  • U2AF1

Fingerprint

Dive into the research topics of 'The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation'. Together they form a unique fingerprint.

Cite this