Codon optimality-mediated mRNA degradation: Linking translational elongation to mRNA stability

Abstract

Messenger RNA (mRNA) translation by the ribosome represents the final step of a complicated molecular dance from DNA to protein. Although classically considered a decipherer that translates a 64-word genetic code into a proteome of astonishing complexity, the ribosome can also shape the transcriptome by controlling mRNA stability. Recent work has discovered that the ribosome is an arbiter of the general mRNA degradation pathway, wherein the ribosome transit rate serves as a major determinant of transcript half-lives. Specifically, members of the degradation complex sense ribosome translocation rates as a function of ribosome elongation rates. Central to this notion is the concept of codon optimality: although all codons impact translation rates, some are deciphered quickly, whereas others cause ribosome hesitation as a consequence of relative cognate tRNA concentration. These transient pauses induce a unique ribosome conformational state that is probed by the deadenylase complex, thereby inducing an orchestrated set of events that enhance both poly(A) shortening and cap removal. Together, these data imply that the coding region of an mRNA not only encodes for protein content but also impacts protein levels through determining the transcript's fate.

Keywords: codon optimality; deadenylation; decapping; genetic code; mRNA degradation; mRNA stability; protein synthesis; ribosomes; translation.

Figure 1.. Definition and Mechanism of Codon Optimality-mediated mRNA Degradation (COMD)

(A) General pathway for eukaryotic mRNA degradation. The first step in mRNA decay occurs by the removal of the 3’ polyadenosine tail by the CCR4/NOT deadenylase complex. This allows for the removal of the 5’ cap structure by the decapping complex and finally digestion of the mRNA body in 5’ to 3’ direction. Alternatively, some mRNAs can also be degraded 3’ to 5’ following deadenylation. (B) Ribosome speed dictates transcript stability through the general mRNA degradation pathway. Slowing ribosome movement is sensed by the mRNA deadenylase complex, eliciting decay of the mRNA. In this example, ribosome speed is determined by codon optimality (a function of tRNA concentrations). (C) Components of the CCR4/NOT complex bind the ribosome near its E-site with NOT5 binding within the E-site itself when both the E-site and A-site are vacant. (D) Cryo-EM structure of NOT5 bound within the ribosome E-site, contacting the P-site tRNA and ribosomal protein S25.

Figure 2.. Disease and Therapeutic Potential

(A) In diseases where specific tRNAs are affected, tRNA levels can be restored to normal levels by expression of siRNAs (small interfering RNAs) or endogenous tRNAs. Goodarzi et al. showed that knocking down tRNA^Arg_CCG and tRNA^Glu_UUC was able to reverse the metastatic progression of cancer cells (Goodarzi et al., 2016), and transgenic expression of functional tRNA^Arg_UCU (n-Tr20) rescued the disease phenotype in mice (Ishimura et al., 2014; Kapur et al., 2020). (B) tRNA therapy may be used to modulate codon optimality and treat haploinsufficiency disorders like Dravet Syndrome, which arises from SCN1A mutation. By ectopically expressing tRNAs that target the non-optimal codons of SCN1A gene, we can increase the translational elongation rate and thereby increase mRNA stability. This would result in increased protein levels and amelioration of the disease.