Site-specific inhibition of translation initiation via 2'-O-methylation.

2'-O-methylation of mRNA selectively inhibits translation initiation at upstream AUG and near-cognate codons, enhancing canonical ORF expression in human transcriptomes.

• Why it matters: Understanding how translation initiation is regulated is crucial because upstream start codons can lead to non-productive or regulatory translation events, impacting gene expression and cellular function.
• What they did: The study analyzed cryo-EM structures to identify hydrogen bonds between mRNA start codons and ribosomal RNA, then used chemical modification to disrupt these interactions at 18 sites, assessing effects on translation.
• The result: Disruption of hydrogen bonds via 2'-O-methylation suppressed upstream translation initiation while promoting canonical ORF translation, revealing a site-specific regulatory mechanism for start codon selection.