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

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.