Matching tRNA modifications in humans to their known and predicted enzymes

Abstract

tRNA are post-transcriptionally modified by chemical modifications that affect all aspects of tRNA biology. An increasing number of mutations underlying human genetic diseases map to genes encoding for tRNA modification enzymes. However, our knowledge on human tRNA-modification genes remains fragmentary and the most comprehensive RNA modification database currently contains information on approximately 20% of human cytosolic tRNAs, primarily based on biochemical studies. Recent high-throughput methods such as DM-tRNA-seq now allow annotation of a majority of tRNAs for six specific base modifications. Furthermore, we identified large gaps in knowledge when we predicted all cytosolic and mitochondrial human tRNA modification genes. Only 48% of the candidate cytosolic tRNA modification enzymes have been experimentally validated in mammals (either directly or in a heterologous system). Approximately 23% of the modification genes (cytosolic and mitochondrial combined) remain unknown. We discuss these 'unidentified enzymes' cases in detail and propose candidates whenever possible. Finally, tissue-specific expression analysis shows that modification genes are highly expressed in proliferative tissues like testis and transformed cells, but scarcely in differentiated tissues, with the exception of the cerebellum. Our work provides a comprehensive up to date compilation of human tRNA modifications and their enzymes that can be used as a resource for further studies.

Figure 1.

tRNA isoacceptors that have been biochemically characterized at the RNA level by traditional methods. Three additional tRNA isoacceptors (Rn-Val-NAC, Hs-Leu-NAA, Hs-Val-NAC) listed in Supplementary Table S1A weren’t placed in this figure due to their unknown nucleotide.

Figure 2.

Cloverleaf representation of tRNA, with modified positions indicated for (A) cytoplasmic and (B) mitochondrial tRNAs, respectively, indicating genes/proteins experimentally validated in human, predicted with high confidence in other species, unknown with predictions, and unknown with no predictions.

Figure 3.

Expression of tRNA modification genes and candidates in a representative set of healthy human tissues. (A) Empirically selected tissues with physiological relevance are included. (B) Like (A), but only representing a set of brain tissues. Genes are clustered according to similarity in the expression profile. Source: gtexportal.org. Genes included are from Supplementary Table S2.