Evolutionarily conserved inhibitory uORFs sensitize Hox mRNA translation to start codon selection stringency

Significance Cellular protein synthesis relies on faithful selection of the translation start codon by the ribosome. Initiation at alternative sites on a messenger RNA (mRNA) impairs production of native proteins, triggers synthesis of junk proteins, and enables regulation of translation. The nucleotide sequence flanking a start codon controls its efficiency of selection. We identify mRNAs containing start codons in conserved poor sequence contexts, including severalHox mRNAs encoding regulators of the body plan. OtherHox mRNAs contain conserved upstream open reading frames with poor start codon contexts that sensitize translation to changes in start codon selection stringency. Thus, alterations in start codon selection stringency has the potential to regulate global gene expression programs, includingHox gene-directed body plan formation in animals.