A rationale for tRNA modification circuits in the anticodon loop

The numerous post-transcriptional modifications of tRNA play a crucial role in tRNA function. While most modifications are introduced to tRNA independently, several sets of modifications are found to be interconnected such that the presence of one set of modifications drives the formation of another modification. The vast majority of these modification circuits are found in the anticodon loop (ACL) region where the largest variety and highest density of modifications occur compared to the other parts of the tRNA and where there is relatively limited sequence and structural information. We speculate here that the modification circuits in the ACL region arise to enhance enzyme modification specificity by direct or indirect use of the first modification in the circuit as an additional recognition element for the second modification. We also describe the five well-studied modification circuits in the ACL, and outline possible mechanisms by which they may act. The prevalence of these modification circuits in the ACL and the phylogenetic conservation of some of them suggest that a number of other modification circuits will be found in this region in different organisms.