Abstract
N6-methyladenosine (m6A) is the most prevalent and internal modification of eukaryotic mRNA. Multiple m6A methylation sites have been identified in the viral RNA genome and transcripts of DNA viruses in recent years. m6A modification is involved in all the phases of RNA metabolism, including RNA stability, splicing, nuclear exporting, RNA folding, translational modulation, and RNA degradation. Three protein groups, methyltransferases (m6A-writers), demethylases (m6A-erasers), and m6A-binding proteins (m6A-readers) regulate this dynamic reversible process. Here, we have reviewed the role of m6A modification dictating viral replication, morphogenesis, life cycle, and its contribution to disease progression. A better understanding of the m6A methylation process during viral pathogenesis is required to reveal novel approaches to combat the virus-associated diseases.
Highlights
Methylation at N6 position of adenosine (m6A) is the most well-characterized and one of the most abundant internal modifications of cellular mRNAs, viral transcripts, long noncoding RNAs, and microRNAs (Fu et al, 2014; Meyer and Jaffrey, 2014)
Kim et al showed that m6A modified nucleotide 8766 near the Hepatitis C virus (HCV) PAMP region reduced retinoic acid-induced gene I (RIG-I) recognition via the sequestration of RNA by YTHDF2 protein (Kim et al, 2020b). These results demonstrate that HCV evades immune response, among other mechanisms, by regulating host m6A machinery
We have discussed the recent advances in identifying the role of m6A methylation in viral life cycles, including both the RNA and DNA viruses. m6A modifications were either supportive or obstructive during viral infections, suggesting a complex pattern of epitranscriptomic regulation of viral gene expression. m6A modification affected viral life cycle in a wide variety of ways affecting disease pathogenesis
Summary
Methylation at N6 position of adenosine (m6A) is the most well-characterized and one of the most abundant internal modifications of cellular mRNAs, viral transcripts, long noncoding RNAs (lncRNAs), and microRNAs (miRNAs) (Fu et al, 2014; Meyer and Jaffrey, 2014). A specialized adaptor protein might target the m6A writer in a distinct set of genes in the chromatin, which can lead to transcript-specificity of m6A methylation (Barbieri et al, 2017; Knuckles et al, 2017; Xiang et al, 2017) Another m6A writer, methyltransferase-like 16 (METTL16), which forms a homodimer, installs m6A in a different sequence and structure context than METTL3/14 complex. Presence of YTHDF2 protein makes the m6A containing mRNA unstable but another class of m6A reader, insulin-like growth factor 2 mRNA-binding proteins (IGF2BP1–3), stabilized the target mRNA in an m6A-dependent manner Another class of m6A reader has been identified, named proline-rich coiled-coil 2A (Prrc2a), which showed preferred binding to methylated probe and stabilized a critical m6A-modified transcript required for myelination. We will summarize the recent studies addressing the role of functional m6A modifications in viral transcripts and genomic RNA of human viruses in the context of replicative viral life cycles and associated disease pathogenesis
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