Transfer RNA methytransferases and their corresponding modifications in budding yeast and humans: activities, predications, and potential roles in human health

Abstract

Throughout the kingdoms of life, transfer RNA (tRNA) undergoes over 100 enzyme-catalyzed, methyl-based modifications. Although a majority of the methylations are conserved from bacteria to mammals, the functions of a number of these modifications are unknown. Many of the proteins responsible for tRNA methylation, named tRNA methyltransferases (Trms), have been characterized in Saccharomyces cerevisiae. In contrast, only a few human Trms have been characterized. A BLAST search for human homologs of each S. cerevisiae Trm revealed a total of 34 human proteins matching our search criteria for an S. cerevisiae Trm homolog candidate. We have compiled a database cataloging basic information about each human and yeast Trm. Every S. cerevisiae Trm has at least one human homolog, while several Trms have multiple candidates. A search of cancer cell versus normal cell mRNA expression studies submitted to Oncomine found that 30 of the homolog genes display a significant change in mRNA expression levels in at least one data set. While 6 of the 34 human homolog candidates have confirmed tRNA methylation activity, the other candidates remain uncharacterized. We believe that our database will serve as a resource for investigating the role of human Trms in cellular stress signaling.

FIG. 1.

The tRNA methyltransferase (Trm) reaction. (A–D) Each reaction diagram shows an example of a methylation reaction for adenine (A), cytosine (B), guanine (C), and uridine (D). In these examples, the methyl group is added to the 1-carbon position of the purine ring (A, C), the 5-carbon position of the pyrimidine ring (B) and the 2′-oxygen position of the ribose sugar (D). The added methyl is in bold. (E) The reactive methyl of S-adenosyl methionine (SAM) is removed by the methyltransferase and added to the substrate, leaving S-adenosyl homocysteine (AdoHcy) as a byproduct. tRNA, transfer RNA.

FIG. 2.

Line diagrams of scTrm1 (A), scTrm2 (B), scTrm3 (C), and their human homolog candidates. The known or predicted methyltransferase domains are in dark gray. Any known or predicted RNA-binding domains are in light gray. Domain assignments are from the protein entries in the NCBI database.

FIG. 3.

Line diagrams of scTrm4 and the hNSUN family. The DNA Topoisomerase II and PUA domains are not believed to be involved with tRNA methylation. PUA, pseudouridine synthase and archeosine transglycolase domain.

FIG. 4.

Line diagrams of scTrm5 (A), scTrm6/61 (B, C), scTrm7 (D), and their human homolog candidates. ScTrm6 and scTrm61 are believed to form a heterotetramer. DUF, domain of unknown function.

FIG. 5.

(A) Line diagrams of scTrm8, scTrm82, and their human homolog candidates. ScTrm8 and scTrm82 are believed to form a heterodimer. (B) Line diagrams of scTrm10 and its human homolog candidates.

FIG. 6.

Line diagrams of scTrm9 (A), scTrm11 (B), scTrm112 (C), and their human homolog candidates. ScTrm112 can dimerize with scTrm9 and scTrm11. hTRMT112 can dimerize with hTRMT11 and hABH8.

FIG. 7.

Line diagrams of scTrm12 (A), scTrm13 (B), scTrm44 (C), scTrm140 (D), and their human homolog candidates. The protein C4ORF23 has recently been renamed METTL19 in its PubMed Gene entry.

FIG. 8.

An overview of known (A) yeast and (B) predicted human homolog tRNA modifications and corresponding enzymes. Each known methylation is marked on the tRNA model with a filled circle and labeled with the enzyme potentially responsible for the methylation. For wybutosine, scTrm12 is one of five proteins responsible (scTyw1-5).