Ending on a high note: Downstream ORFs enhance mRNA translational output

Abstract

Eukaryotic mRNAs were long thought to only translate a single protein product, but it is now recognized that many mRNAs can also encode small open reading frames (ORFs). In this issue of The EMBO Journal, Wu et al characterized small ORFs in the 3' untranslated regions (3' UTRs) of human and zebrafish mRNAs and found that many are indeed translated. The peptides encoded by these downstream ORFs (dORFs) are often poorly conserved across evolution, but many dORFs are nonetheless functional, as the act of their translation can promote translation of the canonical ORF.

Figure 1. Translation of short ORFs controls the efficiency of canonical ORF translation

(A) In eukaryotes, the preinitiation complex (including the 40S small ribosomal subunit, the initiator methionyl‐tRNA, and several additional factors such as the helicase eIF4A) loads at the mRNA 5′ cap and then scans 5′–3′ in search of a start codon. Once the start codon is recognized, the 60S large ribosomal subunit is recruited and the complete 80S ribosome then translates the ORF. (B) Translation of a uORF can block preinitiation complexes from reaching the canonical ORF start codon, thereby down‐regulating the translational output of the mRNA. (C) In contrast, ribosomes can be recruited to the dORFs via cap‐ and scanning‐independent mechanisms, and the act of dORF translation promotes the expression of the canonical ORF.