Translation and mRNA Stability Control

Abstract

Messenger RNA (mRNA) stability and translational efficiency are two crucial aspects of the posttranscriptional process that profoundly impact protein production in a cell. While it is widely known that ribosomes produce proteins, studies during the past decade have surprisingly revealed that ribosomes also control mRNA stability in a codon-dependent manner, a process referred to as codon optimality. Therefore, codons, the three-nucleotide words read by the ribosome, have a potent effect on mRNA stability and provide cis -regulatory information that extends beyond the amino acids they encode. While the codon optimality molecular mechanism is still unclear, the translation elongation rate appears to trigger mRNA decay. Thus, transfer RNAs emerge as potential master gene regulators affecting mRNA stability. Furthermore, while several factors related to codon optimality have been identified in yeast, the orthologous genes in vertebrates do not necessary share the same functions. Here, we discuss codon optimality findings and gene regulation layers related to codon composition in different eukaryotic species. Expected final online publication date for the Annual Review of Biochemistry, Volume 92 is June 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Translation‐coupled mRNA quality control mechanisms

“…This was recently confirmed in mammalian cells in culture, with the use of single‐molecule imaging approaches that revealed translation‐dependent destabilization of mRNA (Dave et al , 2023 ). In addition, the presence of a series of non‐optimal codons can negatively influence protein production by decreasing ribosome translocation rates leading to ribosome collisions that have the potential to trigger RNA quality control pathways and lead to mRNA decay (Hanson & Coller, 2018 ; Wu & Bazzini, 2023 ). This process, known as codon optimality‐mediated mRNA decay (COMD), allows the cell to distinguish between variation in normal translation speeds and terminal ribosome stalling, which triggers alternative RNA quality control pathways (Fig 1B ) (Wu et al , 2019 ; D’Orazio & Green, 2021 ).…”

miR-430 regulates zygotic mRNA during zebrafish embryogenesis

“…The incorporation of s4-UTP measured by SLAM-seq has been taken as way to estimate transcription [ 39 ]; however, this technique relies on the quantification of s4-UTP incorporation in fully processed mature mRNAs. Hence, the level of mature mRNA depends on transcription as well on in mRNA stability [ 31 ]. During zebrafish early development, a zygotically expressed microRNA, miR-430, affects mRNA stability and translation of several maternally provided mRNAs [ 32 , 37 , 40 ].…”

“…Like ZGA, maternal RNA decay occurs in early (zygotic-independent) and late (zygotic-dependent) phases. A handful of factors are commonly deployed in most embryos to coordinate maternal RNA decay phases [ 1 , 22 ], namely, RNA-binding proteins [ 23 , 24 ], RNA modifiers [ 25 – 27 ], RNA secondary structures [ 24 ], codon-optimality [ 28 – 31 ], and microRNAs [ 32 ]. In zebrafish, one of earliest zygotically expressed genes [ 7 , 9 , 33 ] is a post-transcriptional regulator, miR-430, which is necessary for timely clearance of both maternal and maternal-zygotic genes [ 32 ], precise heterochromatin establishment [ 8 ], correct left-right patterning [ 34 ], and proper heart [ 35 ] and brain development [ 36 ].…”

Maternal betaine supplementation ameliorates fatty liver disease in offspring mice by inhibiting hepatic NLRP3 inflammasome activation

“…This might be related to the transcription, processing, and degradation of mRNA, as well as the translation, localization, modification, and programmed disruption of proteins. Protein stably exists after translation, while translation appears to trigger mRNA decay [ 26 ]. In eukaryotes, the cellular concentrations of proteins correlate with the abundances of their corresponding mRNAs, but not strongly, and the correlation coefficient was only 0.40 [ 27 ].…”