## 2 Influence of tRNA Core Modification on tRNA Structure and Stability
### tRNA Core Modifications and Their Impact on tRNA Degradation and Cellular Stability  
As described above, the absence of certain modifications may alter the folding and tertiary structure of tRNAs. The recognition and elimination of these hypomodified tRNAs with compromised tertiary structures are carried out by tRNA quality control pathways. They prevent hypomodified tRNAs from massively entering the translation process. The characterization of the pathways targeting the degradation of tRNAs lacking specific modifications is much more advanced in eukaryotes, but similar mechanisms seem to also exist in bacteria (see below). In eukaryotes, two main pathways for tRNA degradation have been identified: the nuclear surveillance pathway, which primarily degrades defective tRNA precursors (pretRNAs) in the nucleus, and the Rapid tRNA Decay (RTD) pathway, which degrades hypomodified mature tRNAs in the cytoplasm (reviewed in [1]). Nuclear surveillance and RTD degradation pathways have been extensively studied in the yeasts _S. cerevisiae_ and _S. pombe_, where several hypomodified tRNAs have been correlated with phenotypes of thermosensitivity and growth defects (see Table 1 for an overview of the tRNAs targeted by degradation pathways and the tRNA core modifications involved). Early reports showed that yeast pre-tRNA\({}^{\text{Met}}\) lacking m\({}^{1}\)A58 is degraded in the nucleus by the nuclear surveillance pathway [19; 90]. However, a more recent study revealed that a fraction of this hypomodified initiator tRNA continues the maturation process and is exported to the cytoplasm, where it is given a second chance to be degraded by the RTD pathway (Table 1) [91]. The latter study also showed that _S. pombe_ tRNA\({}^{\text{Met}}_{\text{i}}\) lacking m\({}^{1}\)A58 is only degraded by the RTD pathway and not by the nuclear surveillance pathway (Table 1) [91]. As mentioned earlier, m\({}^{1}\)A58 has a drastic impact on the tertiary structure of yeast tRNA\({}^{\text{Met}}_{\text{i}}\), so that the tRNA elbow structure is only properly assembled when this modification is present [70]. This provides a structural explanation of why hypomodified tRNA\({}^{\text{Met}}_{\text{i}}\) lacking m\({}^{1}\)A58 is targeted by RNA decay pathways. This is also in line with a genetic screen, which reported that degradation by the RTD pathway in yeast primarily depends on the structural integrity and stability of the acceptor-stem and T-arm region of tRNAs [92]. Recently, a study reported a new tRNA quality control mechanism in _S. cerevisiae_, in which mature tRNA\({}^{\text{Tyr}}\) lacking m\({}^{1}\)G9 is eliminated by a Met22-dependent but RTD- and nuclear surveillance-independent degradation pathway (Table 1) [93]. Further investigation is definitely needed to identify the nucleases responsible for this degradation and the molecular mechanisms of this intriguing tRNA quality control pathway. Interestingly, m\({}^{1}\)G9 prevents the degradation of tRNA\({}^{\text{Tyr}}\), whereas its absence in tRNA\({}^{\text{Gly}}\) has no effect on its cellular stability [93], adding to the list of known examples of tRNA core modifications that have different effects depending on the tRNA species and are only required for the cellular stability of a particular tRNA [72]. In bacteria, tRNA surveillance and quality control systems monitoring hypomodified and/or thermodynamically destabilized tRNAs have not been studied extensively. These aspects were initially studied in thermophilic bacteria, where tRNA thermal and structural stability are required for optimal cellular thermotolerance and survival at elevated growth temperatures [94]. The tRNA core modifications and their dynamic regulation represent an important player in the structural and thermal adaptation of tRNAs (Figure 3a), and their absence may lead to the targeting of the hypomodified tRNA to quality control pathways. For instance, the lack of m\({}^{7}\)G46 in _T.