Induction of protein aggregation and starvation response by tRNA modification defects
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MINI-REVIEW
Induction of protein aggregation and starvation response by tRNA modification defects Roland Klassen1 · Alexander Bruch1 · Raffael Schaffrath1 Received: 29 July 2020 / Revised: 17 August 2020 / Accepted: 18 August 2020 © The Author(s) 2020
Abstract Posttranscriptional modifications of anticodon loops contribute to the decoding efficiency of tRNAs by supporting codon recognition and loop stability. Consistently, strong synthetic growth defects are observed in yeast strains simultaneously lacking distinct anticodon loop modifications. These phenotypes are accompanied by translational inefficiency of certain mRNAs and disturbed protein homeostasis resulting in accumulation of protein aggregates. Different combinations of anticodon loop modification defects were shown to affect distinct tRNAs but provoke common transcriptional changes that are reminiscent of the cellular response to nutrient starvation. Multiple mechanisms may be involved in mediating inadequate starvation response upon loss of critical tRNA modifications. Recent evidence suggests protein aggregate induction to represent one such trigger. Keywords tRNA modification · Protein aggregation · Decoding · Starvation response
Background During decoding of mRNA, codons are recognized by the tRNA anticodon. For efficient decoding, the tRNA must be correctly folded into an L-shaped structure and the anticodon presented in an unpaired open loop. Posttranscriptional modifications in the anticodon loop are thought to improve codon recognition and contribute to anticodon loop stability by promoting base stacking interactions, reducing the flexibility of the sugar phosphate backbone and preventing unwanted across-the-loop base pairing (Agris 2008; Sokołowski et al. 2017; Väre et al. 2017; Vendeix et al. 2012). For example, tRNALysUUU contains mcm5s2U34 (5-methoxycarbonylmethyl-2-thiouridine at position 34) and ct6A37 (cyclic N6-threonylcarbamoyladenosine at position 37) modifications which each fulfill one or more of these tasks (Johansson et al. 2018; Miyauchi et al. 2013; Schaffrath and Leidel 2017; Thiaville et al. 2014). Both, m cm5s2U and c t6A are formed by multiple biosynthetic enzymes and steps. Completion of m cm5s2U
synthesis is abolished at distinct steps in elp3 and urm1 mutants, while c t6A formation from the t6A (N6-threonylcarbamoyladenosine) precursor requires TCD1 (Huang et al. 2005; Leidel et al. 2009; Miyauchi et al. 2013). Hence, in elp3, urm1 and tcd1 mutants, distinct pathway intermediates are formed at the target nucleosides U34 and A37. Consistent with functional redundancy, joint abrogation of mcm5s2U synthesis at different steps and prevention of t6A to ct6A conversion results in a functional defect of tRNALysUUU normally carrying these modifications (Klassen et al. 2016). A similar functional redundancy exists in the tRNAGlnUUG anticodon loop which naturally carries mcm5s2U and Ψ38 (pseudouridine at position 38) (Han et al. 2015; Klassen et al. 2016). Combined absence of m cm5s2U and Ψ38 in elp3 de
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