From canonical to modified nucleotides: balancing translation and metabolism

Abstract

Every type of nucleic acid in cells may undergo some kind of post-replicative or post-transcriptional chemical modification. Recent evidence has highlighted their importance in biology and their chemical complexity. In the following pages, we will describe new discoveries of modifications, with a focus on tRNA and mRNA. We will highlight current challenges and advances in modification detection and we will discuss how changes in nucleotide post-transcriptional modifications may affect cell homeostasis leading to malfunction. Although, RNA modifications prevail in all forms of life, the present review will focus on eukaryotic systems, where the great degree of intracellular compartmentalization provides barriers and filters for the level at which a given RNA is modified and will of course affect its fate and function. Additionally, although we will mention rRNA modification and modifications of the mRNA 5'-CAP structure, this will only be discussed in passing, as many substantive reviews have been written on these subjects. Here we will not spend much time describing all the possible modifications that have been observed; truly a daunting task. For reference, Bujnicki and coworkers have created MODOMICS, a useful repository for all types of modifications and their associated enzymes. Instead we will discuss a few examples, which illustrate our arguments on the connection of modifications, metabolism and ultimately translation. The fact remains, a full understanding of the long reach of nucleic acid modifications in cells requires both a global and targeted study of unprecedented scale, which at the moment may well be limited only by technology.

A role for a Trypanosoma brucei cytosine RNA methyltransferase homolog in ribosomal RNA processing

“…The presence of modified bases in tRNA has been known for many years. To date, there have been greater than 100 modified bases identified in tRNA including N 1 -methyladenosine, dihydrouridine and 5-methylcytosine (m 5 C) impacting several processes including codon recognition, tRNA charging and reading frame maintenance [ 8 – 10 ]. Similarly, rRNA is extensively modified, and the modifications can impact RNA processing, ribosomal assembly, and/or organismal growth [ 11 ].…”

Prognostic value of comprehensive typing based on m6A and gene cluster

“…Despite advances in treatment, more than 70% of TNBC patients experience recurrence and relapse within three years of surgical resection, resulting in poor prognosis [4]. According to the MODOMICS report, over 160 distinct chemical changes at the posttranscriptional level have been found in various RNAs [5]. Among these chemical changes, N6methyladenosine (m6A), initially described in the 1970s, is the most prevalent and proli c posttranscriptional modi cation in eukaryotic messenger RNA [6].…”

RNA immunoprecipitation to identify in vivo targets of RNA editing and modifying enzymes

“…Base conversions that alter base-pairing and recognition by reverse transcription enzymes, such as Adenosine (A)-to-Inosine (I) editing, can be easily detected in RNA sequencing (RNA-seq) datasets (Ramaswami et al, 2013). However, many RNA modifications are not differentially recognized by reverse transcriptase and thus, methods to detect these changes rely on indirect detection by using chemical treatments that generate bulky adducts to block reverse transcriptase or promote nucleotide misincorporation (Accornero, Ross, & Alfonzo, 2020;Weichmann et al, 2020). The relatively low frequency of occurrence is another challenge to identifying targets of RNA editing and modifying enzymes via searching for changes present in RNA-seq datasets.…”