Some like it translated: small ORFs in the 5'UTR

Exp Cell Res. 2020 Nov 1;396(1):112229. doi: 10.1016/j.yexcr.2020.112229. Epub 2020 Aug 17.


The 5' untranslated region (5'UTR) is critical in determining post-transcriptional control, which is partly mediated by short upstream open reading frames (uORFs) present in half of mammalian transcripts. uORFs are generally considered to provide functionally important repression of the main-ORF by engaging initiating ribosomes, but under specific environmental conditions such as cellular stress, uORFs can become essential to activate the translation of the main coding sequence. In addition, a growing number of uORF-encoded bioactive microproteins have been described, which have the potential to significantly increase cellular protein diversity. Here we review the diverse cellular contexts in which uORFs play a critical role and discuss the molecular mechanisms underlying their function and regulation. The progress over the last decades in dissecting uORF function suggests that the 5'UTR remains an exciting frontier towards understanding how the cellular proteome is shaped in health and disease.

Keywords: 5'UTR; Development and Disease; Gene expression regulation; Translational regulation; uORFs.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • 5' Untranslated Regions*
  • Activating Transcription Factor 4 / genetics
  • Activating Transcription Factor 4 / metabolism
  • Animals
  • Basic-Leucine Zipper Transcription Factors / genetics
  • Basic-Leucine Zipper Transcription Factors / metabolism
  • Eukaryotic Initiation Factors / genetics*
  • Eukaryotic Initiation Factors / metabolism
  • Gene Expression Regulation, Developmental
  • Humans
  • Open Reading Frames*
  • Polymorphism, Genetic
  • Protein Biosynthesis*
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Rats
  • Ribosomes / genetics*
  • Ribosomes / metabolism
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism


  • 5' Untranslated Regions
  • ATF4 protein, human
  • Basic-Leucine Zipper Transcription Factors
  • Eukaryotic Initiation Factors
  • GCN4 protein, S cerevisiae
  • RNA, Messenger
  • Saccharomyces cerevisiae Proteins
  • Activating Transcription Factor 4