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A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3' End

Seung Wook Yang1, Lei Li2, Jon P Connelly1

  • 1Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.

Molecular Cell
|January 26, 2020
PubMed

Insights

Cancer cells shorten mRNA 3' untranslated regions (UTRs) via a mechanism involving the cancer-specific protein MAGE-A11. This protein targets PCF11 for ubiquitination, impacting gene expression and promoting tumor growth.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Genetics

Background:

  • Alternative polyadenylation (APA) generates diverse mRNA isoforms with different 3' UTR lengths.
  • Shortened 3' UTRs (3' US) are prevalent in cancer, but the underlying mechanisms remain unclear.

Purpose of the Study:

  • To elucidate the molecular mechanisms driving 3' US in cancer.
  • To identify the role of cancer-specific proteins in APA regulation.

Main Methods:

  • Investigated the ubiquitination of the mRNA 3' end processing complex protein PCF11.
  • Utilized cancer-specific MAGE-A11-HUWE1 ubiquitin ligase as a key factor.
  • Screened for MAGE-A11 targets and analyzed the impact on mRNA processing complex components.

Main Results:

  • Discovered that MAGE-A11 ubiquitinates PCF11, leading to the dissociation of CFIm25 from the processing complex.
  • Demonstrated that this mechanism drives widespread APA and 3' US in cancer cells.
  • Identified affected transcripts including oncogenes and tumor suppressors like cyclin D2 and PTEN.

Conclusions:

  • MAGE-A11-mediated ubiquitination of PCF11 is a key driver of 3' US in cancer.
  • This pathway contributes to altered expression of critical cancer-related genes.
  • The findings suggest novel therapeutic strategies targeting MAGE-A11 or its associated pathway.
Keywords:
3′ UTR shortening3′ end processing complexCFIm25HUWE1MAGE-A11PCF11PTENalternative polyadenylationcyclin D2ubiquitin

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