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

Mol Cell 2020 Mar 21;77(6):1206-1221.e7. Epub 2020 Jan 21.

Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA. Electronic address:

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.

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2019.12.022DOI Listing
March 2020
14.018 Impact Factor

Publication Analysis

Top Keywords

processing complex
12
mrna processing
12
molecular mechanisms
8
ubiquitin ligase
8
alternative polyadenylation
8
mrna
5
cancers mage-a11
4
re-activated cancers
4
is frequently re-activated
4
germline is frequently
4
male germline
4
cancer cell
4
drive tumorigenesis
4
tumorigenesis screening
4
sufficient drive
4
viability sufficient
4
expressed male
4
cell viability
4
mage-a11 cancer
4
ligase mage-a11
4

Altmetric Statistics

101 Tweets

Similar Publications