Introduction Citation : McGuinness DH , McGuinness D ( 2014 ) m 6 a RNA Methylation : The Implications for Health and Disease

The recent resurgence of interest in m6A has been spurred by some intriguing findings detailing the effects and dynamics of this epigenetic modification. The m6A modification is a highly reactive and fluid modification which can respond rapidly to a broad variety of stimuli, and translate these signals into cellular activity. The little information that has been established on its functional capacity has opened up many new avenues of research and has tremendous implications for several fields of study. Here we outline the breakthroughs which have led to the resurgence of interest in this modification and discuss the effects and potential they represent in terms of control in the immune system, viral replication and infection, as well as the occurrence and progression of cancer. Analysis of nucleic acid modifications and their explicit effects on epigenetic status is a rapidly expanding research arena, one that is growing in stature and importance. Until recently this field had focussed on changes in the chemistry of DNA and the actions of histone proteins and their subsequent modifications. A few key discoveries are set to add a whole new RNA dimension to this exciting field of research, RNA methylation has entered the fray, specifically N-methyl-6-Adenosine – also known as m6A or N6methyladenosine. Although this is not the only RNA modification, over 100 have been identified; it is by far the most abundant [1]. Not only is this modification found extensively in mRNAs it is also found in non-coding RNAs (ncRNAs), including long ncRNAs (lncRNAs) [2]. The m6A modification has been demonstrated to be an internal modification predominantly found in mature mRNA transcripts [2]. Analysis of these transcripts revealed m6A modifications on mRNA transcripts which encoded genes involved in transcriptional regulation, RNA metabolism and signalling cascades [2]. The number of 3’ UTRs of mRNA transcripts demonstrating m6A methylation appear to be above average at two thirds, it should be noted however that accuracy of site detection and methylation state is likely to be more accurate for highly expressed genes than genes with low copy numbers. Around 30% of genes contain microRNA (miRNA) binding sites in the 3’UTRs [3]. Interestingly, where these occur simultaneously the m6A modification is found closer to the stop codon, whereas the miRNA binding site appears to be at the opposite end [2]. Without further information this proximity may well be circumstantial and irrelevant, however the occurrence of both together is higher than would be expected by chance alone. Even more intriguingly, some miRNAs themselves contain a m6A recognition site which may represent a mechanism for their regulation [4]. The m6A modification has been demonstrated in a broad range of species including humans [5], mice [5], virii [6,7], yeast [8-10], bacteria [11] and plants [12]. The methylation reaction is catalysed by a conserved mechanism, based around a multi-component enzymatic complex [13] and counterbalanced by a series of demethylases [14]. Although this multi-component complex has not been elucidated as yet, we postulate that it will behave in a similar manner to other complexes in that it will contain a RNA binding protein (specific for the recognition sequence), although multiple proteins are possible due to the variability of the recognition sequence (12 possible permutations) it seems likely that only 1 or 2 binding proteins are responsible for the core of the complex. Larger numbers of co-factors will determine addition/removal of methylation, leading to several possible complex assemblies. It is also likely that other binding proteins may enhance or repress binding to the recognition sequence or overlapping sites, for example FTO binding sites [15], thus determining which sites are methylation or non-methylated. The recognition sequence for the m6A methylation site is significantly different from other RNA modifications, this sequence has been identified as RRACH (where R = G or A and H = A, C or U) [7,16-20]. Its occurrence has been estimated at 1 in 2000 bases in humans [2,5]. It has been found to be located proximal to stop codons and is highly enriched in the 3’ untranslated region [2]. Like most methylation modifications of nucleotides S-adenosylmethionine (SAM) acts as a methyl group donor for the reaction [21], linking the methylation of RNA to the dynamic equilibrium of this molecule and its associated enzymes. Due to the critical nature of SAM for methylation of both RNA and DNA it is maintained in a highly regulated equilibrium which responds rapidly to cellular factors to maintain idyllic levels. This also suggests that SAM levels are likely to be a driving force for methylation levels via enzyme activity, where availability of SAM drives methylation and low levels of SAM would stimulate demethylation. This is supported by a recently published model suggesting relative methylation levels is determined by Received Date: November 03, 2014 Accepted Date: December 03, 2014 Published Date: December 05, 2014 Volume 1 | Issue 1 Journal of Cancer Science and Clinical Oncology