Structural Insights Into m6A-Erasers: A Step Toward Understanding Molecule Specificity and Potential Antiviral Targeting

The cellular RNA can acquire a variety of chemical modifications during the cell cycle, and compelling pieces of evidence highlight the importance of these modifications in determining the metabolism of RNA and, subsequently, cell physiology. Among myriads of modifications, methylation at the N6-position of adenosine (m(6)A) is the most important and abundant internal modification in the messenger RNA. The m(6)A marks are installed by methyltransferase complex proteins (writers) in the majority of eukaryotes and dynamically reversed by demethylases such as FTO and ALKBH5 (erasers). The incorporated m(6)A marks on the RNA transcripts are recognized by m6A-binding proteins collectively called readers. Recent epigenetic studies have unequivocally highlighted the association of m(6)A demethylases with a range of biomedical aspects, including human diseases, cancers, and metabolic disorders. Moreover, the mechanisms of demethylation by m(6)A erasers represent a new frontier in the future basic research on RNA biology. In this review, we focused on recent advances describing various physiological, pathological, and viral regulatory roles of m(6)A erasers. Additionally, we aim to analyze structural insights into well-known m(6)A-demethylases in assessing their substrate binding-specificity, efficiency, and selectivity. Knowledge on cellular and viral RNA metabolism will shed light on m(6)A-specific recognition by demethylases and will provide foundations for the future development of efficacious therapeutic agents to various cancerous conditions and open new avenues for the development of antivirals.