Post-Transcriptional Modifications of Conserved Nucleotides in the T-Loop of tRNA: A Tale of Functional Convergent Evolution

Abstract

The high conservation of nucleotides of the T-loop, including their chemical identity, are hallmarks of tRNAs from organisms belonging to the three Domains of Life. These structural characteristics allow the T-loop to adopt a peculiar intraloop conformation able to interact specifically with other conserved residues of the D-loop, which ultimately folds the mature tRNA in a unique functional canonical L-shaped architecture. Paradoxically, despite the high conservation of modified nucleotides in the T-loop, enzymes catalyzing their formation depend mostly on the considered organism, attesting for an independent but convergent evolution of the post-transcriptional modification processes. The driving force behind this is the preservation of a native conformation of the tRNA elbow that underlies the various interactions of tRNA molecules with different cellular components.

Reversible RNA phosphorylation stabilizes tRNA for cellular thermotolerance

“…These modifications have critical roles in stabilizing and modulating codon–anticodon interactions on the ribosome, ensuring accurate and efficient protein synthesis. Many RNA modifications are also found in the tRNA body composed of the D-loop, TΨC loop (T-loop) and variable loop (V-loop) 9 , 10 (Fig. 1a ).…”

Different modification pathways for m1A58 incorporation in yeast elongator and initiator tRNAs

“…First, modifications T54, Ѱ55 and m 1 A58 are among the most conserved modified nucleotides in all sequenced tRNAs, together with some dihydrouridines in the D-loop (47,48). They actually participate in maintaining the universal tRNA tertiary fold, more precisely at the level of the elbow region, assembled via conserved contacts between the T- and D-loops (46,49). Second, this modification circuit involves modified nucleotides that are found across the three domains of life, namely Bacteria, Archaea and Eukarya , and which might have been present in the prebiotic soup (50,51).…”

“…Their corresponding modification enzymes probably appeared very early in evolution and were likely present in the common ancestral lineages of Bacteria and Archaea (52,53). However, all the present-day enzymes catalyzing the incorporation of T54, Ѱ55, and m 1 A58 in tRNAs, use different enzymatic strategies and/or correspond to phylogenetically unrelated enzymes between one group of organisms and another, attesting for convergent type of enzyme evolution (49). The fact that the modifications are conserved, but the corresponding enzymes are not, raises the question of whether this circuit of modifications is itself conserved between different organisms.…”

Cooperative methylation of human tRNA3Lys at positions A58 and U54 drives the early and late steps of HIV-1 replication

“…Among the hydrogen bond network within tRNAs, the reverse-Hoogsteen base pair between A58-U54 is one of the most conserved interactions that support the L-shaped tRNA tertiary structure ( 53 ). The m 1 A modification at position 58 stabilizes the A58-U54 reverse Hoogsteen base pair ( 7 ).…”

“…The m 1 A modification at position 58 stabilizes the A58-U54 reverse Hoogsteen base pair ( 7 ). The A58–U54 base pair stacks with the conserved G53–C61 base pair, and the increased hydrophobicity resulting from 5-methylation of m 5 U54 is thought to increase base stacking with G53 ( 53 ). Unlike many tRNA modification enzymes for which knockout cells can be generated without difficulty using the CRISPR/Cas9 system, we did not obtain TRMT61A or TRMT6 knockout cells, implying that TRMT61A and TRMT6 may be essential for human cells.…”