Methylation Modifications in Eukaryotic Messenger RNA

Abstract

RNA methylation modifications have been found for decades of years, which occur at different RNA types of numerous species, and their distribution is species-specific. However, people rarely know their biological functions. There are several identified methylation modifications in eukaryotic messenger RNA (mRNA), such as N7-methylguanosine (m7G) at the cap, N6-methyl-2′-O-methyladenosine (m6Am), 2′-O-methylation (Nm) within the cap and the internal positions, and internal N6-methyladenosine (m6A) and 5-methylcytosine (m5C). Among them, m7G cap was studied more clearly and found to have vital roles in several important mRNA processes like mRNA translation, stability and nuclear export. m6A as the most abundant modification in mRNA was found in the 1970s and has been proposed to function in mRNA splicing, translation, stability, transport and so on. m6A has been discovered as the first RNA reversible modification which is demethylated directly by human fat mass and obesity associated protein (FTO) and its homolog protein, alkylation repair homolog 5 (ALKBH5). FTO has a special demethylation mechanism that demethylases m6A to A through two over-oxidative intermediate states: N6-hydroxymethyladenosine (hm6A) and N6-formyladenosine (f6A). The two newly discovered m6A demethylases, FTO and ALKBH5, significantly control energy homeostasis and spermatogenesis, respectively, indicating that the dynamic and reversible m6A, analogous to DNA and histone modifications, plays broad roles in biological kingdoms and brings us an emerging field “RNA Epigenetics”. 5-methylcytosine (5mC) as an epigenetic mark in DNA has been studied widely, but m5C in mRNA is seldom explored. The bisulfide sequencing showed m5C is another abundant modification in mRNA, suggesting that it might be another RNA epigenetic mark. This review focuses on the main methylation modifications in mRNA to describe their formation, distribution, function and demethylation from the current knowledge and to provide future perspectives on functional studies.