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U2AF35(S34F) Promotes Transformation by Directing Aberrant ATG7 Pre-mRNA 3' End Formation

Sung Mi Park1, Jianhong Ou2, Lynn Chamberlain1

  • 1Howard Hughes Medical Institute, Chevy Chase, MD 20815-6789, USA; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605, USA.

Molecular Cell
|May 18, 2016
PubMed

Insights

Oncogenic U2AF35 mutations in cancer lead to abnormal processing of autophagy gene Atg7 pre-mRNA. This defect causes decreased ATG7 levels, promoting transformation and disease development.

Area of Science:

  • Molecular Biology
  • Cancer Genetics
  • RNA Processing

Background:

  • Recurrent mutations in splicing factor U2AF35 are implicated in cancers and myelodysplastic syndrome (MDS).
  • The precise mechanisms by which oncogenic U2AF35 mutants drive cellular transformation are not fully understood.

Purpose of the Study:

  • To investigate how the oncogenic U2AF35(S34F) mutant transforms cells.
  • To identify aberrantly processed pre-mRNAs in U2AF35(S34F)-transformed cells.

Main Methods:

  • Generation of cell lines transformed by the U2AF35(S34F) mutant.
  • Deep sequencing to identify aberrant pre-mRNA processing.
  • Analysis of autophagy-related factor 7 (Atg7) pre-mRNA processing and ATG7 protein levels.

Main Results:

  • U2AF35(S34F) transformation results in abnormal processing of Atg7 pre-mRNA, specifically through selection of a distal cleavage and polyadenylation (CP) site.
  • This leads to a longer Atg7 mRNA variant with inefficient translation, causing decreased ATG7 levels and an autophagy defect.
  • MDS and acute myeloid leukemia patient samples with U2AF35(S34F) mutations exhibit increased usage of the ATG7 distal CP site.

Conclusions:

  • The U2AF35(S34F) mutation promotes transformation by disrupting Atg7 pre-mRNA processing, leading to an autophagy defect.
  • This defect predisposes cells to secondary mutations, contributing to cancer development.
  • The findings reveal a novel mechanism for U2AF35 oncogenic activity in myeloid malignancies.

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