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 (m⁶ A) 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.

Keywords: 5-methylcytosine; N6-methyladenosine; RNA modification; epitranscriptomic mark; mRNA; miRNA; rRNA; tRNA.

Figure 1

Overview of the most commonly used existing techniques to map m⁵C in RNA

Figure 2

Distribution of identified m⁵C sites in different RNA types. Left, m⁵C positions are marked on a model tRNA. They reside in the acceptor stem (C72), the variable loop region (C47‐C50), the anticodon stem (C38) and the anticodon loop (C34), respectively. Middle, symbolic depiction of the frequency of occurrence of m⁵C along a model mRNA deduced from studies in mouse and humans. Dashed lines mark the translational start and stop codons, respectively. Right, m⁵C positions identified in the 28S/25S rRNA of the large ribosomal subunit and in the 12 rRNA of the small subunit of the mitochondrial ribosome, respectively, are shown. E, P and A sites of the ribosome are symbolized. While the positions of the m⁵C sites in the large ribosomal subunit have been approximately placed according to their position in the ribosomal crystal structure, the m⁵C in the small subunit is shown in an arbitrary location

Figure 3

Overview of the different known RCMTs in eukaryotes. The enzymes are grouped according to their substrate preference shown at the bottom part of the figure. The most important consequences of methylation are named in the text at the top