Journal
CELL
Volume 149, Issue 3, Pages -Publisher
CELL PRESS
DOI: 10.1016/j.cell.2012.03.022
Keywords
-
Categories
Funding
- ERC (European Research Council)
- KWF (Dutch cancer foundation)
- Horizon
- VICI-NWO (Nederlandse Organisatie voor Wetenschappelijk Onderzoek)
- CBG (Centre for Biomedical Genetics)
- SNF (The Swiss National Science Foundation)
- VENI-NWO
- Wellcome Trust
Ask authors/readers for more resources
Alternative cleavage and polyadenylation (APA) is emerging as an important layer of gene regulation. Factors controlling APA are largely unknown. We developed a reporter-based RNAi screen for APA and identified PABPN1 as a regulator of this process. Genome-wide analysis of APA in human cells showed that loss of PABPN1 resulted in extensive 30 untranslated region shortening. Messenger RNA transcription, stability analyses, and in vitro cleavage assays indicated enhanced usage of proximal cleavage sites (CSs) as the underlying mechanism. Using Cyclin D1 as a test case, we demonstrated that enhanced usage of proximal CSs compromises microRNA-mediated repression. Triplet-repeat expansion in PABPN1 (trePABPN1) causes autosomal-dominant oculopharyngeal muscular dystrophy (OPMD). The expression of trePABPN1 in both a mouse model of OPMD and human cells elicited broad induction of proximal CS usage, linked to binding to endogenous PABPN1 and its sequestration in nuclear aggregates. Our results elucidate a novel function for PABPN1 as a suppressor of APA.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available