Do all modifications benefit all tRNAs?

Abstract

Despite the universality of tRNA modifications, some tRNAs lacking specific modifications are subject to degradation pathways, while other tRNAs lacking the same modifications are resistant. Here, we suggest a model in which some modifications have minor, possibly redundant, roles in specific tRNAs. This model is consistent with the low specificity of some modification enzymes. Limitations of this model include the limited assays and growth conditions on which these conclusions are based, as well as the high specificity exhibited by many modification enzymes with important roles in translation. The specificity of these enzymes is often enhanced by complex substrate recognition patterns and sub-cellular compartmentalization.

Fig. 1

Illustration of the specificity of the rapid tRNA degradation pathway. The figure depicts four yeast tRNAs known to have m⁷G₄₆ and m⁵C₄₉, only one of which is a substrate for the rapid tRNA decay pathway in trm8-Δ trm4-Δ mutants, which lack these modifications. Mature tRNA^Val(AAC) is rapidly degraded in trm8-Δ trm4-Δ mutants upon shift to 37 °C by the 5′-3′ exonucleases Rat1 or Xrn1, whereas tRNA^Phe, tRNA^Val(CAC), and tRNA_i^Met are resistant. Green circles represent each residue, yellow circles represent known modifications, orange circles represent sites of m⁷G and m⁵C modification, and the anticodon is colored to match its amino acid, indicated by an oval.

Fig. 2

The role of intracellular localization on tRNA modification specificity. In eukaryotes there are three locations where tRNAs can be modified: the nucleus, cytoplasm and organelles (chloroplasts and mitochondria). Highlighted here are two examples where localization may impact tRNA modification. In the case of cytoplasmic thiolation, only tRNA^Gln, tRNA^Glu and tRNA^Lys with a U at position 34 are substrates for thiolation. In some cases like the example of tRNA^Trp in trypanosomes, thiolation occurs at an unusual position (U₃₃) following import into the mitochondria. Thus tRNA^Trp transits through the nucleus and is only a thiolation substrate for the mitochondrial enzymes. Likewise, this tRNA only undergoes C to U editing following mitochondrial import, suggesting the requirement for mitochondria-specific modifications for editing, and highlighting the possible interrelation among different modifications in the same substrate. Nifs refers to the universally conserved desulfurase involved in tRNA thiolation in all organisms. UBLs are the ubiquitin-like factors involved in cytoplasmic thiolation. Mtu is the mitochondrial homolog of the bacterial mnmA, responsible for transferring the sulfur to tRNAs. The question mark denotes the fact that the C to U editing enzyme still remains unknown.