Trm112, a Protein Activator of Methyltransferases Modifying Actors of the Eukaryotic Translational Apparatus

Abstract

Post-transcriptional and post-translational modifications are very important for the control and optimal efficiency of messenger RNA (mRNA) translation. Among these, methylation is the most widespread modification, as it is found in all domains of life. These methyl groups can be grafted either on nucleic acids (transfer RNA (tRNA), ribosomal RNA (rRNA), mRNA, etc.) or on protein translation factors. This review focuses on Trm112, a small protein interacting with and activating at least four different eukaryotic methyltransferase (MTase) enzymes modifying factors involved in translation. The Trm112-Trm9 and Trm112-Trm11 complexes modify tRNAs, while the Trm112-Mtq2 complex targets translation termination factor eRF1, which is a tRNA mimic. The last complex formed between Trm112 and Bud23 proteins modifies 18S rRNA and participates in the 40S biogenesis pathway. In this review, we present the functions of these eukaryotic Trm112-MTase complexes, the molecular bases responsible for complex formation and substrate recognition, as well as their implications in human diseases. Moreover, as Trm112 orthologs are found in bacterial and archaeal genomes, the conservation of this Trm112 network beyond eukaryotic organisms is also discussed.

To be or not to be modified: Miscellaneous aspects influencing nucleotide modifications in tRNAs

“…The second class consists of enzymes that modify only a subset of tRNAs having the correct target nucleotide at the position to be modified. This class includes the Trm11 enzyme from yeast, which is responsible for the synthesis of m 2 G10 in tRNAs in association with the ubiquitous partner protein Trm112 that is also required for the function of other methyltransferases . The m 2 G10 modification is found in approximately half of the tRNAs, although all yeast tRNAs have a G at position 10 (Fig.…”

Evolutionary insights into Trm112-methyltransferase holoenzymes involved in translation between archaea and eukaryotes

“…In eukaryotes, the same motif of eRF1 is modified by a complex formed by the Mtq2 methyltransferase (MTase) catalytic subunit and its activator Trm112 subunit ( 19 , 20 , 24–27 ). Interestingly, in Saccharomyces cerevisiae , the Trm112 protein also interacts with and activates three other MTases, namely Bud23, Trm9 and Trm11, which modify factors involved in translation ( 28 ). The Bud23–Trm112 complex and its human ortholog (BUD23-TRMT112 or WBSCR22-TRMT112) catalyze the N7-methylation of G nucleotide (m 7 G) at positions 1575 and 1639 on the yeast and human 18S rRNA, respectively, and these complexes are essential for 40S biogenesis ( 29–35 ).…”

“…Bioinformatics analyses have revealed the presence of Trm112 orthologues in bacteria and archaea suggesting that its role might extend outside eukaryotic organisms ( 25 , 28 , 36 ). While nothing is known on bacterial Trm112 orthologues, the detection of Mtq2, Trm9 and Trm11 orthologues in archaeal genomes together with the strong similarity between eukaryotic and archaeal translation machineries suggest that archaeal Trm112 might play a role similar to the eukaryotic Trm112 ( 53–55 ).…”

Monitoring the 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U) modification in eukaryotic tRNAs via the γ-toxin endonuclease

“…In S. cerevisiae, the heterodimeric Trm9-Trm112 complex catalyzes the final formation of the methoxycarbonylmethyl side chain in mcm5s2U (Mazauric et al 2010;Chen et al 2011a). Trm9 is the catalytic methyltransferase subunit while Trm112 is required for enzymatic activity by serving as a platform for tRNA interaction and cofactor binding (Letoquart et al 2015;Bourgeois et al 2017) However, the activities of the predicted enzymes remain unverified in most cases. Thus, we investigated whether the γ-toxin assay could be used to validate the methyltransferase activities of Trm9 and Trm112 homologs.…”

“…The multisubunit Elongator complex is required for early steps of mcm5U formation through the generation of 5-carbonylmethyluridine (cm5U) and 5-carbamoylmethyluridine (ncm5U) via a proposed enzymatic reaction involving acetyl-CoA (for reviews, seed Karlsborn et al 2014b;Dauden et al 2017;Kolaj-Robin and Seraphin 2017). The cm5U and/or ncm5U modification is then further modified by a heterodimeric methyltransferase complex consist-ing of the Trm9 enzymatic subunit and the Trm112 structural protein (Kalhor and Clarke 2003;Mazauric et al 2010;Liger et al 2011;Letoquart et al 2015;Bourgeois et al 2017). In a subset of tRNAs, the mcm5U base can undergo even further modification by the Ncs2-Ncs6 thiolase to generate the final mcm5s2U modification (Dewez et al 2008;Huang et al 2008;Leidel et al 2009;Noma et al 2009;Nakai et al 2017).…”