Mistranslation: from adaptations to applications

• Published in: Biochimica et biophysica acta. General subjects Vol. 1861; no. 11; pp. 3070 - 3080
• Main Authors: Hoffman, Kyle S., O'Donoghue, Patrick, Brandl, Christopher J.
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.11.2017
• Subjects: accidents; Adaptation, Biological - genetics; Adaptive response; alleles; amino acids; Animals; biomedical research; Codon - genetics; Evolution; Evolution, Molecular; Genetic Code; Humans; metagenomics; Mistranslation; Mutation - physiology; nucleotide sequences; Polymorphism, Genetic - physiology; Protein Biosynthesis - genetics; Protein Engineering - methods; Protein Engineering - trends; proteins; proteome; proteomics; selection pressure; sequence analysis; synthetic biology; Transfer RNA; Translation; translation (genetics); Mistranslation; Genetic code; Evolution; Translation; Adaptive response; Transfer RNA
• ISSN: 0304-4165; 1872-8006
• DOI: 10.1016/j.bbagen.2017.01.031

The conservation of the genetic code indicates that there was a single origin, but like all genetic material, the cell's interpretation of the code is subject to evolutionary pressure. Single nucleotide variations in tRNA sequences can modulate codon assignments by altering codon-anticodon pairing or tRNA charging. Either can increase translation errors and even change the code. The frozen accident hypothesis argued that changes to the code would destabilize the proteome and reduce fitness. In studies of model organisms, mistranslation often acts as an adaptive response. These studies reveal evolutionary conserved mechanisms to maintain proteostasis even during high rates of mistranslation. This review discusses the evolutionary basis of altered genetic codes, how mistranslation is identified, and how deviations to the genetic code are exploited. We revisit early discoveries of genetic code deviations and provide examples of adaptive mistranslation events in nature. Lastly, we highlight innovations in synthetic biology to expand the genetic code. The genetic code is still evolving. Mistranslation increases proteomic diversity that enables cells to survive stress conditions or suppress a deleterious allele. Genetic code variants have been identified by genome and metagenome sequence analyses, suppressor genetics, and biochemical characterization. Understanding the mechanisms of translation and genetic code deviations enables the design of new codes to produce novel proteins. Engineering the translation machinery and expanding the genetic code to incorporate non-canonical amino acids are valuable tools in synthetic biology that are impacting biomedical research. This article is part of a Special Issue entitled "Biochemistry of Synthetic Biology - Recent Developments" Guest Editor: Dr. Ilka Heinemann and Dr. Patrick O’Donoghue. •The genetic code is subject to evolutionary pressure.•tRNA sequence variation alters the genetic code.•Mistranslation is an adaptive response.•Genetic code expansions enhance therapeutic proteins.•tRNAs have therapeutic potential.