Impact of Chemical Modification ontRNAFunction

Abstract

Post‐transcriptional tRNA modifications play a critical role in ensuring a high‐quality pool of tRNA for participation in cellular translation. Despite their importance, important questions remain about the impacts of individual tRNA modifications on tRNA structure and function. Similarly, biological consequences of the absence of tRNA modifications have begun to be characterised in detail only recently. tRNA modifications have important impacts on biology, ranging from important impacts on individual tRNA molecules, to powerful effects on cellular function, and finally important roles in human health and disease. Key Concepts tRNA modifications occur at high frequency and with great chemical diversity. tRNA modifications fine‐tune tRNA structure and function. Through their effects on individual tRNA molecules, the impacts of tRNA modifications propagate to the cellular and organismal levels. tRNA modifications can regulate translation and impact protein homeostasis. Lack of tRNA modifications has been implicated in human diseases, such as neurological disorders, glucose metabolic defects and cancer.

A tRNA-specific function for tRNA methyltransferase Trm10 is associated with a new tRNA quality control mechanism inSaccharomyces cerevisiae

“…However, inactivation of other players in the known tRNA decay pathways in S. cerevisiae did not similarly rescue the trm10Δ 5FU growth defect ( Figure 4 ), indicating that Met22 acts through some other yet unknown tRNA decay pathway to remove inappropriately modified tRNA Trp from the cells. The fact that Trm10 modifies 13 different cytosolic tRNAs in S. cerevisiae , but that the biological importance of the m 1 G9 modification seems to only be significant for one of its substrates (tRNA Trp ) provides yet another example of a tRNA modification that does not impact all the tRNAs that contain it equally (Phizicky and Alfonzo 2010; Howell and Jackman 2019). The evolutionary origins and molecular basis for the activity of Trm10 on multiple S. cerevisiae tRNAs remains to be fully understood.…”

“…tRNA modifications found in the body of the tRNA, however, are performed by enzymes that often display mild to no obvious phenotypes when their genes are deleted in model systems such as S. cerevisiae . Recently, many of these genes have been implicated in more subtle roles that are often specific to unique tRNA species (Phizicky and Alfonzo 2010; Jackman and Alfonzo 2013; Howell and Jackman 2019; Phizicky and Hopper 2023). In cases studied so far, tRNA body modifications are generally thought to improve overall tRNA folding and stability and thus aid the tRNA in evading degradation by quality control pathways that remove low-quality tRNA from the pool of molecules available for translation (Whipple et al 2011; Hopper and Huang 2015; Phizicky and Hopper 2023).…”

Diversity in Biological Function and Mechanism of the tRNA Methyltransferase Trm10

“…Body modifications generally exhibit a more indirect yet important role in tRNA folding and stability, while also playing a part in tRNA quality control to ensure a functional pool of tRNA molecules is maintained. 4,5 In S. cerevisiae, there are 10 chemically unique modifications found in the tRNA body region while the ACL region contains the majority of remaining tRNA modifications. 5,6 The chemical diversity of tRNA nucleotide base and ribose modifications is vast, ranging from addition of relatively "simple" chemical groups via acetylation or methylation, to more profound chemical and structural changes with complex modifications such as queuosine or wybutosine.…”

“…tRNA modifications are generally categorized into two regions of tRNA structure: body modifications and anticodon stem− loop (ACL) modifications. 4,5 Modifications to the ACL frequently aid in the efficiency or fidelity of translation, while body modifications have been more challenging to understand due to their distant location from the site of codon−anticodon interaction. Body modifications generally exhibit a more indirect yet important role in tRNA folding and stability, while also playing a part in tRNA quality control to ensure a functional pool of tRNA molecules is maintained.…”

“…tRNA modifications are generally categorized into two regions of tRNA structure: body modifications and anticodon stem–loop (ACL) modifications. , Modifications to the ACL frequently aid in the efficiency or fidelity of translation, while body modifications have been more challenging to understand due to their distant location from the site of codon–anticodon interaction. Body modifications generally exhibit a more indirect yet important role in tRNA folding and stability, while also playing a part in tRNA quality control to ensure a functional pool of tRNA molecules is maintained. , In S. cerevisiae , there are 10 chemically unique modifications found in the tRNA body region while the ACL region contains the majority of remaining tRNA modifications. , The chemical diversity of tRNA nucleotide base and ribose modifications is vast, ranging from addition of relatively “simple” chemical groups via acetylation or methylation, to more profound chemical and structural changes with complex modifications such as queuosine or wybutosine. , Base methylation, the focus of this Account, comprises 8 chemically unique modifications of cytoplasmic tRNAs in S. cerevisiae : 1-methylguanosine (m 1 G), 2-methylguanosine (m 2 G), N 2 , N 2 -dimethylguanosine (m 2,2 G), 7-methylguanosine (m 7 G), 1-methyladenine (m 1 A), 3-methylcytidine (m 3 C), 5-methylcytidine (m 5 C), and 1-methylinosine (m 1 I) (Figure ). Many of these modifications and their corresponding enzymes are conserved in Eukarya, Bacteria, and Archaea. ,− …”