Division of labor in epitranscriptomics: What have we learnt from the structures of eukaryotic and viral multimeric RNA methyltransferases?

Abstract

The translation of an mRNA template into the corresponding protein is a highly complex and regulated choreography performed by ribosomes, tRNAs and translation factors. Most RNAs involved in this process are decorated by multiple chemical modifications (known as epitranscriptomic marks) contributing to the efficiency, the fidelity and the regulation of the mRNA translation process. Many of these epitranscriptomic marks are written by holoenzymes made of a catalytic subunit associated with an activating subunit. These holoenzymes play critical roles in cell development.Indeed, several mutations being identified in the genes encoding for those proteins are linked to human pathologies such as cancers and intellectual disorders for instance. This review describes the structural and functional properties of RNA methyl-

Molecular mechanism of tRNA binding by the Escherichia coli N7 guanosine methyltransferase TrmB

“…5 and 6 ), is not conserved in B. subtilis, S. cerevisiae or human TrmB homologs, and the N-terminal region present in mesophilic TrmB proteins is entirely absent in A. aeolicus TrmB. Notably, TrmB is one of several tRNA modification enzymes that utilizes only a single subunit in bacteria but requires an auxiliary protein for catalysis in eukaryotes ( 45 , 46 ). As such, a similar difference in tRNA affinity may exist for other bacterial tRNA modification enzymes and their eukaryotic two-subunit homologs.…”

Molecular mechanism of tRNA binding by theEscherichia coliN7 guanosine methyltransferase TrmB

“…Moreover, the R26 residue, that we demonstrate here to be important for tRNA binding (Table 1, Figure 5), is not conserved in B. subtilis or S. cerevisiae TrmB homologs, and the N-terminal region present in mesophilic TrmB proteins is entirely absent in A. aeolicus TrmB. Notably, TrmB is one of several tRNA modification enzymes that utilizes only a single subunit in bacteria but requires an auxiliary protein for catalysis in eukaryotes (43,44). As such, a similar difference in tRNA affinity may exist for other bacterial tRNA modification enzymes and their eukaryotic two-subunit homologs.…”

The impact of tRNA modifications on translation in cancer: identifying novel therapeutic avenues

“…Furthermore, this study highlighted that both THUMPD3 and TRMT11 are indispensable for m 2 G introduction in tRNAs, emphasizing their crucial role in optimal protein synthesis and cell proliferation ( 111 ). Both proteins interact with the allosteric regulator of methyltransferases, tRNA methyltransferase activator subunit 11-2 (TRMT112) ( 112 , 113 ), known for its interaction with other enzymes that also has a profound impact in tumor growth and translation alteration, such as ALKBH8 or TRMT9A, TRMT9B and methyltransferase 5 (METTL5) ( 114–116 ), emphasizing the intricate network of interactions crucial for cellular processes such as protein synthesis and proliferation.…”