Research Papers: Gerotarget (Focus on Aging):
Dysfunctional transcripts are formed by alternative polyadenylation in OPMD
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Vered Raz1, George Dickson2 and Peter A.C. ’t Hoen1
1 Department of Human Genetics, Leiden University Medical Centre, Leiden, The Netherlands
2 School of Biological Science, Royal Holloway University of London, Egham, Surrey, United Kingdom
Vered Raz, email:
Keywords: PABPN1, mRNA processing, alternative polyadenylation site, autophagy, aging muscles, Gerotarget
Received: April 11, 2017 Accepted: August 03, 2017 Published: September 05, 2017
Post-transcription mRNA processing in the 3’-untranslated region (UTR) of transcripts alters mRNA landscape. Alternative polyadenylation (APA) utilization in the 3’-UTR often leads to shorter 3’-UTR affecting mRNA stability, a process that is regulated by PABPN1. In skeletal muscles PABPN1 levels reduce with age and a greater decrease in found in Oculopharyngeal muscular dystrophy (OPMD). OPMD is a late onset autosomal dominant myopathy caused by expansion mutation in PABPN1. In OPMD models a shift from distal to proximal polyadenylation site utilization in the 3’-UTR, and PABPN1 was shown to play a prominent role in APA. Whether PABPN1-mediated APA transcripts are functional is not fully understood. We investigate nuclear export and translation efficiency of transcripts in OPMD models. We focused on autophagy-regulated genes (ATGs) with APA utilization in cell models with reduced functional PABPN1. We provide evidence that ATGs transcripts from distal PAS retain in the nucleus and thus have reduced translation efficiency in cells with reduced PABPN1. In contrast, transcripts from proximal PAS showed a higher cytoplasmic abundance but a reduced occupancy in the ribosome. We therefore suggest that in reduced PABPN1 levels ATG transcripts from APA may not effectively translate to proteins. In those conditions we found constitutive autophagosome fusion and reduced autophagy flux. Augmentation of PABPN1 restored autophagosome fusion, suggesting that PABPN1-mediated APA plays a role in autophagy in OPMD and in aging muscles.
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