acp³U: A Conserved RNA Modification with Lessons Yet to Unfold

RNA modifications are highly conserved across all domains of life, suggesting an early emergence and a fundamental role in cellular processes. The modification 3-(3-amino-3-carboxypropyl)uridine (acp³U) is found in tRNAs of eukaryotes and prokaryotes, and in the 16S rRNA of archaea. In eukaryotic rRNA, a complex modification containing the acp group, m¹acp³Ψ is present at the analogous position. Although this modification was first identified in tRNA in 1969, only recently have the enzymes responsible for the synthesis of this modification on tRNA been identified. Despite its deep evolutionary conservation, the biological role of acp³U on tRNAs remains elusive. In Escherichia coli, it may contribute to genomic stability, while in human cells, loss of both tRNA acp³U-modifying enzymes impairs cell growth, though the underlying mechanisms are not yet understood. The conservation and multifunctionality of acp³U highlight the broader challenges of elucidating the roles of tRNA modifications in cellular homeostasis.