Posttranscriptional RNA Modifications: Playing Metabolic Games in a Cell’s Chemical Legoland

Abstract

SUMMARY Nature combines existing biochemical building blocks, at times with subtlety of purpose. RNA modifications are a prime example of this, where standard RNA nucleosides are decorated with chemical groups and building blocks that we recall from our basic biochemistry lectures. The result: a wealth of chemical diversity whose full biological relevance has remained elusive despite being public knowledge for some time. Here, we will highlight a number of modifications that, because of their chemical intricacy, rely on seemingly unrelated pathways to provide co-factors for their synthesis. Besides their immediate role in affecting RNA function, modifications may act as sensors and transducers of information that connect a cell's metabolic state to its translational output, carefully orchestrating a delicate balance between metabolic rate and protein synthesis at a system's level.

The RNA modification landscape in human disease

“…On the other hand, the lack of specific RNA modifications may affect global and/or local translation rates, and consequently cause increased protein aggregation (Nedialkova and Leidel 2015). Finally, it has also been proposed that RNA modifications transduce information that connect the cell's metabolic state to its translational output, and therefore, that their dysregulation may cause an imbalance between metabolic rates and protein synthesis (Helm and Alfonzo 2014). Future work will be needed to disentangle the causal relationship between RNA modification dysregulation and human disease.…”

Protein folding and tRNA biology

“…The three cases are clear examples of the links between tRNA modification and the cellular metabolic state. Indeed, most of the modifications require ubiquitous metabolites and co-enzymes for the transfer of methyl groups, acetyl groups, amino acids, isoprenoids, sugars, etc., that are crucial at the crossroads of basic metabolic pathways: S-adenosyl methionine (a major methyl donor), thiamine pyrophosphate, riboflavin, pyridoxal phosphate, biotin, folic acid, cyanocobalamin, among others (Helm and Alfonzo 2014). The cellular concentration of some of these compounds varies by several folds, depending on the metabolic state and the cellular fate (Fernández-Arroyo et al 2015).…”

“…They include: methyl-transferases, adenosine-deaminases, pseudouridine synthetases, thiouridylases, and transglycosylases, among others (for a complete list of enzymes, see http://modomics.genesilico.pl; Machnicka et al 2013). Most of the modifications take place directly on the nucleosides included in the tRNA (Helm and Alfonzo 2014). Some specific modifications are introduced by transglycosylation, replacing a base of the target tRNA by a modified base, which, in turn, could be further modified in situ once incorporated into the tRNA.…”

The identification and characterization of non-coding and coding RNAs and their modified nucleosides by mass spectrometry

“…18 The discovery of agmatidine, cyanomethyluridine and these geranylated uridines is consistent with the cellular use of metabolic intermediates and products as reagents for RNA modification. 19 A rather unique example of an RNA modification that appears to have been overlooked for many years was reported by Suzuki and colleagues.…”