Anticodon stem-loop tRNA modifications influence codon decoding and frame maintenance during translation

Abstract

RNAs are central to protein synthesis, with ribosomal RNA, transfer RNAs and messenger RNAs comprising the core components of the translation machinery. In addition to the four canonical bases (uracil, cytosine, adenine, and guanine) these RNAs contain an array of enzymatically incorporated chemical modifications. Transfer RNAs (tRNAs) are responsible for ferrying amino acids to the ribosome, and are among the most abundant and highly modified RNAs in the cell across all domains of life. On average, tRNA molecules contain 13 post-transcriptionally modified nucleosides that stabilize their structure and enhance function. There is an extensive chemical diversity of tRNA modifications, with over 90 distinct varieties of modifications reported within tRNA sequences. Some modifications are crucial for tRNAs to adopt their L-shaped tertiary structure, while others promote tRNA interactions with components of the protein synthesis machinery. In particular, modifications in the anticodon stem-loop (ASL), located near the site of tRNA:mRNA interaction, can play key roles in ensuring protein homeostasis and accurate translation. There is an abundance of evidence indicating the importance of ASL modifications for cellular health, and in vitro biochemical and biophysical studies suggest that individual ASL modifications can differentially influence discrete steps in the translation pathway. This review examines the molecular level consequences of tRNA ASL modifications in mRNA codon recognition and reading frame maintenance to ensure the rapid and accurate translation of proteins.