Abstract
The addition of a methyl group to the N6 position of adenosine (m6A) is the most common posttranscriptional RNA modification, and it regulates most steps of RNA metabolism including splicing, stability, translation, nuclear-export, and RNA structures. Besides cellular RNA, m6A modifications have also been detected on viral RNA. A range of recent studies have demonstrated the crucial roles of m6A in the virus–host interactions; however, m6A cellular machineries are only characterized in limited mammalian species. Herein, we aim to present comprehensive evolutionary insights into major m6A writers, erasers, and readers and draw a comparative structural analysis between avian and mammalian m6A-associated machineries. The comparative collinearity on the chromosomal scale revealed that the majority of m6A-related genes were found less syntenic even among avian species. Genetic analysis of avian m6A erasers revealed a distinct phylogenetic clustering compared to mammalian orthologs and shared a weak percent (55%) identity with mammalian species with low identity percentage (55%). The overall comparative three-dimensional (3D) structure analyses among different mammalian species were maintained through synonymous structural mutations. Unlike erasers, the putative 3D structures in the active sites as for the aromatic cage in YTH-domain of YTHDC1 and two pivotal loops in MTD-domains in METTL3 exhibited structural alterations in chicken. In conjunction with in silico investigations, influenza viruses significantly downregulated gene the transcription of m6A writers and erasers, whereas m6A readers were moderately regulated in chicken fibroblasts. In light of these findings, future detailed biochemical and crystallographic studies are warranted to define the roles of m6A machinery in regulating both viral and cellular RNA metabolism in avian species.
Highlights
The cellular RNA plays an integral role in the cell life cycle
The methylation at N6 position of adenosine (m6A)-related orthologs distribution revealed that they were allocated in various chromosomes that were designated by their chromosome number (Figure 1)
Vis-à-vis human, the relative order of some orthologs (YTHDF3 and methyltransferase like-3 (METTL3)) was maintained in mouse chromosomes 3 and 14, respectively whereas some orthologs shared the same chromosome number with chicken such as YTHDF1, YTHDC1, and methyltransferase like-14 (METTL14) that located at chromosomes 20, 4, and 4, respectively, (Figure 1)
Summary
The cellular RNA plays an integral role in the cell life cycle. Posttranscriptional modifications include capping, splicing, and polyadenylation. More than 100 different chemical modifications have been described in various forms of RNAs: tRNA, rRNA, lncRNA, and mRNA. These modifications, collectively referred to as epitranscriptome, display an extensive landscape and affect. The chemical modifications integrated in the mRNA of eukaryotes are attributed to different canonical bases: adenosine (m1A; Li et al, 2017; Safra et al, 2017) and cytosine (m5C; Motorin et al, 2009). Non-canonical bases accept modifications as well: pseudouridine (Carlile et al, 2014) and inosine (Levanon et al, 2004). The most prominent and enriched in RNA modifications is methylation at N6 position of adenosine (m6A; Dominissini et al, 2012; Boccaletto et al, 2018)
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