Molecular Cell
Volume 77, Issue 6, 19 March 2020, Pages 1206-1221.e7
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Article
A Cancer-Specific Ubiquitin Ligase Drives mRNA Alternative Polyadenylation by Ubiquitinating the mRNA 3′ End Processing Complex

https://doi.org/10.1016/j.molcel.2019.12.022Get rights and content
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Highlights

  • MAGE-A11 is aberrantly expressed in cancer and is a potent oncogene

  • MAGE-A11-HUWE1 ubiquitin ligase promotes ubiquitination and degradation of PCF11

  • MAGE-A11 promotes alternative polyadenylation and 3′ UTR shortening in cancer

  • MAGE-A11-induced 3′ UTR shortening modulates core oncogenes and tumor suppressors

Summary

Alternative polyadenylation (APA) contributes to transcriptome complexity by generating mRNA isoforms with varying 3′ UTR lengths. APA leading to 3′ UTR shortening (3′ US) is a common feature of most cancer cells; however, the molecular mechanisms are not understood. Here, we describe a widespread mechanism promoting 3′ US in cancer through ubiquitination of the mRNA 3′ end processing complex protein, PCF11, by the cancer-specific MAGE-A11–HUWE1 ubiquitin ligase. MAGE-A11 is normally expressed only in the male germline but is frequently re-activated in cancers. MAGE-A11 is necessary for cancer cell viability and is sufficient to drive tumorigenesis. Screening for targets of MAGE-A11 revealed that it ubiquitinates PCF11, resulting in loss of CFIm25 from the mRNA 3′ end processing complex. This leads to APA of many transcripts affecting core oncogenic and tumor suppressors, including cyclin D2 and PTEN. These findings provide insights into the molecular mechanisms driving APA in cancer and suggest therapeutic strategies.

Keywords

MAGE-A11
HUWE1
ubiquitin
alternative polyadenylation
PCF11
3′ end processing complex
CFIm25
cyclin D2
PTEN
3′ UTR shortening

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These authors contributed equally

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