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Abstract
Alternative polyadenylation (APA)-mediated 3′-untranslated region (UTR) shortening is known to increase protein expression due to the loss of miRNA regulatory sites. Yet, mRNAs with longer 3′-UTR also show enhanced protein expression. Here, we identify a mechanism by which longer transcripts generated by the distal-most APA site leads to increased protein expression compared to the shorter transcripts and the longer transcripts are positioned to regulate heart failure (HF). A Star-PAP target gene, NQO1 has three poly(A) sites (PA-sites) at the terminal exon on the pre-mRNA. Star-PAP selects the distal-most site that results in the expression of the longest isoform. We show that the NQO1 distal-specific mRNA isoform accounts for the majority of cellular NQO1 protein. Star-PAP control of the distal-specific isoform is stimulated by oxidative stress and the toxin dioxin. The longest NQO1 transcript has increased poly(A) tail (PA-tail) length that accounts for the difference in translation potentials of the three NQO1 isoforms. This mechanism is involved in the regulation of cardiac hypertrophy (CH), an antecedent condition to HF where NQO1 downregulation stems from the loss of the distal-specific transcript. The loss of NQO1 during hypertrophy was rescued by ectopic expression of the distal- but not the proximal- or middle-specific NQO1 mRNA isoforms in the presence of Star-PAP expression, and reverses molecular events of hypertrophy in cardiomyocytes.
Highlights
Almost all eukaryotic mRNAs are polyadenylated at the 3 -end in a coupled process - endonucleolytic cleavage at the PA-site followed by the addition of a poly(A) tail (PA-tail) of up to 250 adenosine residues in the nucleus [1,2,3]
We reported that Star-poly(A) polymerases (PAP) regulates genome-wide APA where it preferentially controls the distal PA-sites on the target 3 -untranslated region (UTR) [44]
We show a new mechanism of APA operating at least at the NQO1 3 -UTR that is critical for protein expression during cardiac hypertrophy (CH), an antecedent condition to incident heart failure (HF)
Summary
Almost all eukaryotic mRNAs are polyadenylated at the 3 -end in a coupled process - endonucleolytic cleavage at the PA-site followed by the addition of a PA-tail of up to 250 adenosine residues in the nucleus [1,2,3]. Identification of a nuclear non-canonical PAP, Star-PAP (Speckle targeted PIPKI␣ regulated PAP) indicated the existence of selective polyadenylation in the nucleus [5]. Star-PAP forgoes the use of some of the cleavage factors involved in the canonical polyadenylation and instead associates with a unique set of factors. These factors include phosphatidyl inositol 4 phosphate 5 kinase type I alpha (PIPKI␣) that generates the lipid messenger phosphatidyl inositol-4,5-bisphosphate (PI4,5P2), RNA binding motif protein 10 (RBM10), casein kinase I␣ and ε (CKI␣/ε), and protein kinase C␦ (PKC␦) that regulate Star-PAP function [7,8,9,10,11]. The precise fraction of mRNAs targeted by Star-PAP likely depends upon the cell type and signals that are impacting those cells [5,9,10,11,12]
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