Dysfunctional transcripts are formed by alternative polyadenylation in OPMD. / Raz, Vered; Dickson, John; 't Hoen, Peter A. C.

In: Oncotarget, Vol. 8, No. 43, 05.09.2017, p. 73516-73528.

Research output: Contribution to journalArticlepeer-review

Published

Standard

Dysfunctional transcripts are formed by alternative polyadenylation in OPMD. / Raz, Vered; Dickson, John; 't Hoen, Peter A. C.

In: Oncotarget, Vol. 8, No. 43, 05.09.2017, p. 73516-73528.

Research output: Contribution to journalArticlepeer-review

Harvard

APA

Vancouver

Author

Raz, Vered ; Dickson, John ; 't Hoen, Peter A. C. / Dysfunctional transcripts are formed by alternative polyadenylation in OPMD. In: Oncotarget. 2017 ; Vol. 8, No. 43. pp. 73516-73528.

BibTeX

@article{513c78daeccc4c39a981c3325f52c209,
title = "Dysfunctional transcripts are formed by alternative polyadenylation in OPMD",
abstract = "Post-transcription mRNA processing in the 3{\textquoteright}-untranslated region (UTR) of transcripts alters mRNA landscape. Alternative polyadenylation (APA) utilization in the 3{\textquoteright}-UTR often leads to shorter 3{\textquoteright}-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{\textquoteright}-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.",
author = "Vered Raz and John Dickson and {'t Hoen}, {Peter A. C.}",
year = "2017",
month = sep,
day = "5",
doi = "10.18632/oncotarget.20640",
language = "English",
volume = "8",
pages = "73516--73528",
journal = "Oncotarget",
issn = "1949-2553",
publisher = "Impact Journals",
number = "43",

}

RIS

TY - JOUR

T1 - Dysfunctional transcripts are formed by alternative polyadenylation in OPMD

AU - Raz, Vered

AU - Dickson, John

AU - 't Hoen, Peter A. C.

PY - 2017/9/5

Y1 - 2017/9/5

N2 - 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.

AB - 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.

U2 - 10.18632/oncotarget.20640

DO - 10.18632/oncotarget.20640

M3 - Article

VL - 8

SP - 73516

EP - 73528

JO - Oncotarget

JF - Oncotarget

SN - 1949-2553

IS - 43

ER -