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Engineering Artificial Factors to Specifically Manipulate Alternative Splicing in Human Cells
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The splicing factor U2AF1 contributes to cancer progression through a noncanonical role in translation regulation

Murali Palangat1, Dimitrios G Anastasakis2, Dennis Liang Fei3

  • 1Laboratory of Receptor Biology and Gene Expression, National Cancer Insitute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Genes & Development
|March 8, 2019
PubMed

Insights

Somatic mutations in U2AF1, a spliceosome component, affect cancer. The S34F mutation disrupts U2AF1

Area of Science:

  • Molecular Biology
  • Oncology
  • Genetics

Background:

  • Somatic mutations in spliceosome genes are common in neoplasms.
  • U2AF1 mutations, particularly S34F, affect splice site selection and mRNA splicing.
  • The oncogenic role of U2AF1 mutations remains unclear.

Purpose of the Study:

  • To investigate the noncanonical functions of U2AF1 and the impact of the S34F mutation.
  • To elucidate the role of U2AF1 in mRNA translation regulation.

Main Methods:

  • Polysome profiling to assess mRNA translation.
  • Analysis of U2AF1's interaction with mature mRNA in the cytoplasm.

Main Results:

  • U2AF1 directly binds mature mRNA in the cytoplasm, negatively regulating translation.
  • The S34F mutation alters this function, affecting hundreds of mRNAs.
  • Increased synthesis of interleukin 8 (IL-8) was observed, promoting metastasis and inflammation.

Conclusions:

  • U2AF1 has a splicing-independent role in regulating mRNA translation.
  • The S34F mutation contributes to oncogenesis by dysregulating translation and promoting IL-8 synthesis.
  • Targeting U2AF1's noncanonical function may offer new therapeutic strategies for cancer.
Keywords:
IL8U2AF1myeloid leukemiasplicing factor mutationstranslation regulator

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