Ribosome slowdown triggers codon‐mediated mRNA decay independently of ribosome quality control

Abstract

The control of mRNA stability plays a central role in regulating gene expression patterns. Recent studies have revealed that codon composition in the open reading frame determines mRNA stability in multiple organisms. Based on genome‐wide correlation approaches, this previously unrecognized role for the genetic code is attributable to the kinetics of the codon‐decoding process by the ribosome. However, complementary experimental analyses are required to clarify the codon effects on mRNA stability and the related cotranslational mRNA decay pathways, for example, those triggered by aberrant ribosome stalling. In the current study, we performed a set of reporter‐based analyses to define codon‐mediated mRNA decay and ribosome stall‐dependent mRNA decay in zebrafish embryos. Our analysis showed that the effect of codons on mRNA stability stems from the decoding process, independent of the ribosome quality control factor Znf598 and stalling‐dependent mRNA decay. We propose that codon‐mediated mRNA decay is rather triggered by transiently slowed ribosomes engaging in a productive translation cycle in zebrafish embryos.

iCodon customizes gene expression based on the codon composition

“…In agreement with no significant correlation between the stability of the injected mRNA and codon adaptation index (Supplemental Fig. 2 B), a recent work showed that codon optimality is a better predictor of mRNA stability than codon usage in zebrafish 46 . Therefore, iCodon provides a practical first step toward more targeted solutions.…”

Synonymous codon usage regulates translation initiation

“…The factors that are reported to bind to these states all have the potential to repress translation initiation. For instance, in yeast, Not5p binds the empty E-site and helps recruit deadenylation machinery; given the link between deadenylation and translational repression, it could be that Not5p (CNOT3, in humans) also represses translation initiation (Buschauer et al, 2020, Veltri et al, 2021, Mishima et al, 2022). An alternative is the recruitment of EDF1/GIGYF2/4EHP, which are known to recognize collided ribosomes as part of the RQC pathway and repress translation initiation on those substrates (Brandman, O., and Hegde, 2016, Hickey et al, 2020, Juszkiewicz et al, 2020, Sinha et al, 2020, Wu et al, 2020).…”

“…Finally, recent work has shown that slow elongation, specifically through nonoptimal codon usage and slow decoding, triggers mRNA decay by a mechanism distinct from the RQC pathway (Buschauer et al, 2020, Veltri et al, 2021, Mishima et al, 2022). Best described in yeast, this pathway is mediated by the CCR4-NOT deadenylase complex (Presnyak et al, 2015, Hanson et al, 2018, Buschauer et al, 2020).…”

Specific recognition and ubiquitination of slow-moving ribosomes by human CCR4-NOT

“…In eukaryotes, mRNAs with sub-optimal codons are subjected to a specialized "codon-optimality decay" pathway (2,3) and codon usage is a major determinant of mRNA half-life (4)(5)(6)(7)(8)(9)(10)(11)(12)(13). Interestingly, slow translation and thus low codon-optimality may be sensed directly by the conserved multi-functional cytoplasmic deadenylase CCR4-NOT (14,15).…”