Suboptimal codon pairs trigger ribosome collisions and cellular quality control responses in tRNA modification...

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Transfer RNA (tRNA) modifications are crucial for accurate protein synthesis and co-translational folding.
• The precise mechanisms by which tRNA modifications influence codon optimality and cellular phenotypes are not fully understood.

Purpose of the Study:

• To investigate how wobble uridine (U34) modifications in tRNA affect ribosome dynamics and cellular responses.
• To elucidate the role of specific U34 modifications, like 5-carbamoylmethyluridine (ncm5U), in decoding.

Main Methods:

• High-resolution ribosome profiling was employed to analyze ribosome behavior.
• Analysis of wobble uridine (U34) modification mutants to observe effects on translation.

Main Results:

• Ribosomes stall at specific codon pairs in U34 modification mutants, leading to ribosome collisions.
• These collisions activate ribosome-associated quality control (RQC) pathways, degrading aberrant peptides and mRNAs.
• Specific U34 modifications, such as ncm5U, have distinct effects at the A and P sites of the ribosome.
• Only a subset of codons decoded by hypomodified tRNA show reduced decoding speed, indicating context-dependent effects.

Conclusions:

• Loss of tRNA modifications primarily impacts the translation rate of suboptimal codons.
• Cellular surveillance systems, including RQC and chaperone pathways, are coordinated to maintain protein homeostasis.
• These findings highlight the adaptability of cellular quality control in response to disruptions in tRNA modification.