The dynamic RNA modification 5‐methylcytosine and its emerging role as an epitranscriptomic mark

Abstract

It is a well‐known fact that RNA is the target of a plethora of modifications which currently amount to over a hundred. The vast majority of these modifications was observed in the two most abundant classes of RNA, rRNA and tRNA. With the recent advance in mapping technologies, modifications have been discovered also in mRNA and in less abundant non‐coding RNA species. These developments have sparked renewed interest in elucidating the nature and functions of those “epitransciptomic” modifications in RNA. N6‐methyladenosine (m6A) is the best understood and most frequent mark of mRNA with demonstrated functions ranging from pre‐mRNA processing, translation, miRNA biogenesis to mRNA decay. By contrast, much less research has been conducted on 5‐methylcytosine (m5C), which was detected in tRNAs and rRNAs and more recently in poly(A)RNAs. In this review, we discuss recent developments in the discovery of m5C RNA methylomes, the functions of m5C as well as the proteins installing, translating and manipulating this modification. Although our knowledge about m5C in RNA transcripts is just beginning to consolidate, it has become clear that cytosine methylation represents a powerful mechanistic strategy to regulate cellular processes on an epitranscriptomic level. This article is categorized under: RNA Processing > RNA Editing and Modification RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > tRNA Processing RNA Turnover and Surveillance > Regulation of RNA Stability

The ribosomal RNA m5C methyltransferase NSUN-1 modulates healthspan and oogenesis inCaenorhabditis elegans

“…NSUN-1 is also a member of the NOP2/Sun RNA methyltransferase family. Since there are only two known m 5 C residues on worm 26S rRNA (Sharma and Lafontaine, 2015; Trixl and Lusser, 2019), one of them at C2381, being installed by NSUN-5, we speculated that NSUN-1 might be required for introducing the second m 5 C residue at position C2982. Notably, both 26S m 5 C sites are localized close to important functional regions of the ribosome, and they are highly conserved during evolution (Fig.…”

Multiple links between 5-methylcytosine content of mRNA and translation

“…The merits of using bsRNA-seq to discover m 5 C sites transcriptome-wide have been controversially discussed (Legrand et al 2017;Linder and Jaffrey 2019;Motorin and Helm 2019;Trixl and Lusser 2019). We contend that the bsRNA-seq approach as presented here is fit-for-purpose as it is based on a combination of efficient bisulfite reaction conditions, bespoke read mapping and conservative site calling from replicate data.…”

“…Transcriptome-wide m 5 C maps at variable depth are by now available for several tissues and cell lines of human/mouse (Squires et al 2012;Hussain et al 2013b;Khoddami and Cairns 2013;Blanco et al 2016;Amort et al 2017;Legrand et al 2017;Yang et al 2017;Wei et al 2018;Chen et al 2019;Huang et al 2019;Sun et al 2019), zebrafish (Yang et al 2019b), plant (Cui et al 2017;David et al 2017;Yang et al 2019a), archaeal (Edelheit et al 2013) and even viral (Courtney et al 2019a;Courtney et al 2019b) origin, persistently identifying sites with biased distribution in mRNAs and/or ncRNAs, reviewed in (Trixl and Lusser 2019). Several studies have further suggested regulatory roles for m 5 C in mRNAs.…”

Multiple links between 5-methylcytosine content of mRNA and translation

“…Transcriptome-wide m 5 C maps at variable depth are by now available for several tissues and cell lines of human/ mouse [9,37,[45][46][47][48][49][50][56][57][58][59], zebrafish [51], plant [60][61][62], archaeal [63], and even viral [64,65] origin, persistently identifying sites with biased distribution in mRNAs and/or ncRNAs, reviewed in [66]. Several studies have further suggested regulatory roles for m 5 C in mRNAs.…”

“…Imperfections of each method have been noted, for example, in m 5 C-RIP, antibody specificity is crucial, while for miCLIP and Aza-IP, sensitivity might not reach lower abundance targets. All this can account for inconsistencies in site detection across different methods [10,66]. bsRNAseq is not completely specific to m 5 C (e.g.…”