Translational recoding by chemical modification of non-AUG start codon ribonucleotide bases
Yoshihiko Fujita1, Takeru Kameda2,3,4, Chingakham Ranjit Singh5
1Center for iPS Cell Research and Application, Kyoto University, Sakyo-ku, Kyoto 606-8507, Japan.
Science Advances
|April 8, 2022
Summary
Chemical modifications to start codons in eukaryotes can alter translation initiation. 5-cytosine methylation and pseudouridylation create a prokaryotic-like preference for GUG and UUG over CUG start codons.
Area of Science:
- Molecular Biology
- Epigenetics
- Translational Control
Background:
- Eukaryotic translation typically initiates at AUG start codons, with non-AUG codons like CUG showing lower initiation frequencies.
- Prokaryotes utilize permissive start codons such as GUG and UUG, unlike eukaryotes.
Purpose of the Study:
- To investigate the impact of combined 5-cytosine methylation (5mC) and pseudouridylation (Ψ) on non-AUG start codon usage in eukaryotic translation.
- To understand how these modifications influence the preference for GUG, UUG, and CUG initiation codons.
Main Methods:
- Analysis of eukaryotic translation initiation frequencies with modified non-AUG start codons.
- Molecular dynamics simulations of tRNA anticodon pairing to modified codons within the ribosomal preinitiation complex.
- Assessment of the role of eukaryotic initiation factor 1 in codon:anticodon interactions.
Main Results:
- Combined 5mC and Ψ modifications shifted eukaryotic translation initiation preference towards GUG and UUG, favoring them over CUG.
- Pseudouridylation (Ψ) enhanced GUG and UUG initiation by modifying the second base of the codon.
- 5-cytosine methylation (5mC) reduced CUG initiation by modifying the first base of the codon.
- Ψ universally increased codon:anticodon pairing affinity, mitigating eukaryotic initiation factor 1's discrimination against non-AUG codons.
Conclusions:
- Chemical modifications of start codon bases provide a novel mechanism for regulating translational control in eukaryotes.
- This modification-driven translational control offers a new layer for proteome diversity regulation.
- These findings have implications for the development of therapeutic mRNA technologies.
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