Before It Gets Started: Regulating Translation at the 5' UTR

Abstract

Translation regulation plays important roles in both normal physiological conditions and diseases states. This regulation requires cis-regulatory elements located mostly in 5' and 3' UTRs and trans-regulatory factors (e.g., RNA binding proteins (RBPs)) which recognize specific RNA features and interact with the translation machinery to modulate its activity. In this paper, we discuss important aspects of 5' UTR-mediated regulation by providing an overview of the characteristics and the function of the main elements present in this region, like uORF (upstream open reading frame), secondary structures, and RBPs binding motifs and different mechanisms of translation regulation and the impact they have on gene expression and human health when deregulated.

Figure 1

Regulatory elements present in 5′ UTR.

Figure 2

Translational regulation by RNA binding proteins. (a) In iron-deficient cells, IRPs bind to the IRE localized in the 5′ UTR of ferritin mRNA, blocking its translation. Once cellular iron levels increase, a complex containing Fe binds to IRPs. Thus, these proteins are allosterically modified, which reduces IRP-IRE binding and allows the translation of ferritin mRNAs. (b) msl-2 gene regulation in females flies. After transcription in the nucleus, SXL specifically binds to intronic U-rich regions of msl-2 pre-mRNA and inhibits the intron removal (1). In the cytoplasm, SXL binds to the same elements localized now in the 5′ UTR of mature msl-2 mRNA, enhances the translation initiation of a upstream ORF (2), and prevents the main ORF translation (3). The regulatory elements in the 3′ UTR of msl-2 mRNA were not represented.

Figure 3

Impact of uAUG sequences on translation regulation. (a) Comparison of luciferase levels obtained for constructs having the 5′ UTR of the gene ACT (control) and genes containing uAUG: WBSCR16, MFSD5, and BCL2L13. (b) Deletion or mutation of uAUG sequence present in genes WBSCR16, MFSD5 and BCL2L13 reverts translation repression as seen as an increase in luciferase activity.