The helicase Ded1p controls use of near-cognate translation initiation codons in 5' UTRs

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• The DEAD-box RNA helicase Ded1p (yeast) and DDX3 (mammalian) are essential for translation initiation.
• Dysregulation of DDX3 is implicated in cancer and intellectual disabilities, and DDX3 is a target for viral infections.
• The precise mechanism by which Ded1p/DDX3 interacts with RNA during translation initiation remains unclear.

Purpose of the Study:

• To elucidate the role of Ded1p in RNA engagement during translation initiation.
• To investigate the link between Ded1p activity, mRNA structure, and alternative translation start codon usage.
• To understand the physiological relevance of this regulatory program in processes such as meiosis.

Main Methods:

• Integrated transcriptome-wide analyses of translation, RNA structure, and Ded1p-RNA binding.
• Assessed the impact of repressing Ded1p activity on 5' untranslated region (UTR) RNA structure and translation initiation.
• Examined Ded1p levels and alternative translation initiation during meiosis.

Main Results:

• Ded1p associates with the translation pre-initiation complex at the mRNA entry channel.
• Repressing Ded1p activity leads to increased RNA structure in 5' UTRs, promoting translation initiation from upstream near-cognate start codons.
• Ded1p repression results in decreased protein synthesis from main open reading frames and activates alternative translation initiation sites during meiosis.

Conclusions:

• Ded1p regulates translation initiation by controlling the selection of near-cognate start codons positioned near mRNA structures in 5' UTRs.
• A regulatory program linking Ded1p, near-cognate start codon activation, and mRNA structure governs protein synthesis.
• This Ded1p-mediated regulation plays a significant role in cellular processes, including meiosis.