Regulation and dysregulation of 3'UTR-mediated translational control

Abstract

Translational control provides numerous advantages in regulation of gene expression including rapid responsiveness, intracellular localization, nondestruction of template mRNA, and coordinated regulation of transcript ensembles. Transcript-selective, translational control is driven by the specific interaction of factor(s) with the 5' or 3' untranslated region (UTR), thereby influencing initiation, elongation, or termination of mRNA translation. The mean length of human 3'UTRs is greater than that of 5'UTR, indicating the expanded potential for motifs, structural elements, and binding sites for trans-acting factors that exert transcript-selective translation control. New and unexpected mechanisms of 3'UTR-mediated translational control and their contributions to disease have received increasing attention during the last decade. Here, we briefly review a few recent and representative discoveries of 3'UTR-mediated translational control, emphasizing the novel aspects of these regulatory mechanisms and their potential pathophysiological significance.

Figure 1

Multi-modal control of mRNA translation by the 3′UTR. Shown is 3′UTR-mediated translational control by cis-acting structural RNA elements, i.e., GAIT and BAT elements and their cognate trans-acting factors, i.e., heterotetrameric GAIT complex and BAT complex; miRNA-mediated translational control; 3′UTR shortening by alternative polyadenylation (APA); generation of truncated, 3′UTR-less open reading frame (ORF) by polyadenylation-mediated Tyr-to-stop codon conversion (PAY*); and translational control by competitive binding of a trans-acting factor to a sequence-specific element, i.e., hnRNPL-binding to CARE, for secondary regulation of protein- and miRNA-mediated translational control. Some of these regulatory processes might be facilitated by end-to-end mRNA closure mediated by interaction of polyA-binding protein (PABP) with the polyA tail and with the translation initiation complex.