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Genes Dev. 2019 Mar 6. doi: 10.1101/gad.319590.118. [Epub ahead of print]

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

Author information

1
Laboratory of Receptor Biology and Gene Expression, National Cancer Insitute, National Institutes of Health, Bethesda, Maryland 20892, USA.
2
National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
3
Weill Cornell Medicine, New York, New York 10065, USA.
4
Laboratory of Myeloid Malignancies, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
5
Computational Biology Program, Public Health Sciences and Biological Sciences, Fred Hutchinson Cancer Center, Seattle, Washington 98109, USA.

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.

KEYWORDS:

IL8; U2AF1; myeloid leukemia; splicing factor mutations; translation regulator

PMID:
30842218
DOI:
10.1101/gad.319590.118

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