Transfer RNA: A dancer between charging and mis-charging for protein biosynthesis

Abstract

Transfer RNA plays a fundamental role in the protein biosynthesis as an adaptor molecule by functioning as a biological link between the genetic nucleotide sequence in the mRNA and the amino acid sequence in the protein. To perform its role in protein biosynthesis, it has to be accurately recognized by aminoacyl-tRNA synthetases (aaRSs) to generate aminoacyl-tRNAs (aa-tRNAs). The correct pairing between an amino acid with its cognate tRNA is crucial for translational quality control. Production and utilization of mis-charged tRNAs are usually detrimental for all the species, resulting in cellular dysfunctions. Correct aa-tRNAs formation is collectively controlled by aaRSs with distinct mechanisms and/or other trans-factors. However, in very limited instances, mis-charged tRNAs are intermediate for specific pathways or essential components for the translational machinery. Here, from the point of accuracy in tRNA charging, we review our understanding about the mechanism ensuring correct aa-tRNA generation. In addition, some unique mis-charged tRNA species necessary for the organism are also briefly described. The central role of tRNA is to establish genetic code by coupling an mRNA codon with an amino acid [1,2]. Besides this canonical function, it also carries out a wide range of non-aminoacylation functions such as cell wall biosynthesis, anti-biotic synthesis, protein degradation, bacterial membrane lipid modification, virus replication, apoptosis, amino acid biosynthesis, and precursor of small regulatory RNA, which are collectively designated non-canonical functions and have been previously reviewed elsewhere [3][4][5][6][7][8].

A deafness-associated tRNAAspmutation alters the m1G37 modification, aminoacylation and stability of tRNAAspand mitochondrial function

“…The mutation is localized at a highly conserved nucleotide (A37), adjacent to the 3′ end of the anticodon of the mt–tRNA Asp (22,23). The nucleotide at position 37 of the tRNAs are often modified by methylthiolation (28,29).…”

“…A failure to aminoacylate tRNA properly then makes the mutant mt–tRNA Asp to be metabolically less stable and more subject to degradation, thereby lowering the level of this tRNA, as in the case of m.3243A > G mutation in the mt–tRNA Leu(UUR) (42,53). Alternatively, the m.7551A > G mutation likely affects the formation of functional structure of tRNAs and thus makes the tRNA be more unstable (22,23). In the present study, 42% reduction in the steady-state level of mt–tRNA Asp observed in mutant cybrids was consistent with the previous observations in the lymphoblastoid cell lines carrying the m.4435A > G mutation in the tRNA Met gene (32,33).…”

“…The most prevalent mtDNA mutations associated with syndromic deafness are the MELAS-associated m.3243A > G mutation in the mt–tRNA Leu(UUR) gene (13) and MERRF-associated m.8344A > G mutation in the mt–tRNA Lys gene (14), while the nonsyndromic deafness-associated mtDNA mutations included the mt–tRNA Ser(UCN) 7445A > G, 7472insC, 7505T > C and 7511T > C, mt–tRNA His 12201T > C, mt–tRNA Gly 10003T > C and mt–tRNA Ile 4295A > G mutations (15–21). These mt–tRNA mutations altered their structures and functions, including the processing of the mt–tRNA from the primary transcripts, stability of the folded secondary structure, the charging of the mt–tRNA, or the codon–anticodon interaction in the process of translation (5,22,23). The m.7445A > G mutation altered the processing of the 3′ end mt–tRNA Ser(UCN) precursor (24), the m.7511T > C mutations affected the stability of mt-tRNA Ser(UCN) (25) and m.12201T > C mutation altered the aminoacylation of mt–tRNA His (20).…”

“…As shown in Figure 1, the m.7551A > G mutation is localized at a highly conserved nucleotide (A37), adjacent (3′) to the anticodon of mt–tRNA Asp (22,23). There were no modifications of i 6 A37 or t 6 A37 in the human mitochondrial tRNA Asp (27), although the nucleotides at position 37 (A or G) of tRNAs are often modified by methylthiolation (28–29).…”

Self-protective responses to norvaline-induced stress in a leucyl-tRNA synthetase editing-deficient yeast strain

“…For most aaRSs, the aminoacylation reaction occurs in two steps: amino acid activation and tRNA aminoacylation. In more detail, aaRSs use adenosine triphosphate (ATP) to activate amino acid by generating aminoacyl-adenylate (aa-AMP) intermediates, and the aminoacyl moiety is then transferred to the tRNA to form aminoacyl-tRNA (aa-tRNA) (1,2). Since many amino acids and some of their metabolic intermediates share similar structures, there is the potential for a specific aaRS to mischarge non-cognate amino acids; and to counteract this and ensure translation fidelity, many aaRSs use a ‘double-sieve’ mechanism to eliminate non-cognate amino acids (3,4).…”