Queuosine glycosylation protects against stress-induced tRNA fragmentation and modulates cleavage site selection
Schwarzer, A.;Dietzsch, J.;Stille, S.;Lemus-Diaz, N.;Erich, M.;Schoeller, E.;Sievers, K.;Dickmanns, A.;Ficner, R.;Bohnsack, K.;Hoebartner, C.;Bohnsack, M.
Show abstract
Alongside their canonical function as adaptors in translation, tRNAs are precursors of tRNA-derived fragments that can regulate diverse aspects of gene expression. Queuosine (Q), present at position 34 of eukaryotic tRNAAsn/Asp/His/Tyr, has been implicated in suppressing tRNA fragmentation. In vertebrates, Q34 of tRNAAsp and tRNATyr is further modified by mannosylation and galactosylation, respectively, catalyzed by QTMAN and QTGAL. However, the interplay between these glycosylations and other anticodon loop modifications, and their impact on tRNA fragmentation, have remained unclear. Here, we define a modification circuit in human tRNAAsp in which Q34 stimulates DNMT2-dependent m5C38 formation, while subsequent Q34 mannosylation does not impact m5C38 installation; reciprocally, m5C38 inhibits Q34 incorporation by the tRNA-guanine transglycosylase TGT. By contrast, anticodon loop modifications of tRNATyr are installed independently, although our data support a hierarchical pathway in which TRMT5-mediated m1G37 formation precedes queuosinylation and galactosylation. Alongside demonstrating that Q34 glycosylation enhances protein synthesis, our data reveal that mannosylation of Q34 protects tRNAAsp from stress-induced cleavage, thus expanding the relevance of Q glycosylation beyond translation.
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