Structural Insights Into m6A-Erasers: A Step Toward Understanding Molecule Specificity and Potential Antiviral Targeting
Open Access
- 12 January 2021
- journal article
- review article
- Published by Frontiers Media SA in Frontiers in Cell and Developmental Biology
Abstract
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 (m6A) is the most important and abundant internal modification in the messenger RNA. The m6A 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 m6A marks on the RNA transcripts are recognized by m6A-binding proteins collectively called readers. Recent epigenetic studies have unequivocally highlighted the association of m6A demethylases with a range of biomedical aspects, including human diseases, cancers, and metabolic disorders. Moreover, the mechanisms of demethylation by m6A 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 m6A erasers. Additionally, we aim to analyze structural insights into well-known m6A-demethylases in assessing their substrate binding-specificity, efficiency, and selectivity. Knowledge on cellular and viral RNA metabolism will shed light on m6A-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.Funding Information
- Biotechnology and Biological Sciences Research Council
This publication has 145 references indexed in Scilit:
- ALKBH4-dependent demethylation of actin regulates actomyosin dynamicsNature Communications, 2013
- A variant in FTO shows association with melanoma risk not due to BMINature Genetics, 2013
- ALKBH5 Is a Mammalian RNA Demethylase that Impacts RNA Metabolism and Mouse FertilityMolecular Cell, 2013
- N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTONature Chemical Biology, 2011
- The AlkB Domain of Mammalian ABH8 Catalyzes Hydroxylation of 5‐Methoxycarbonylmethyluridine at the Wobble Position of tRNAAngewandte Chemie, 2010
- Human AlkB homologue 1 (ABH1) exhibits DNA lyase activity at abasic sitesDNA Repair, 2010
- Oxidative demethylation of 3‐methylthymine and 3‐methyluracil in single‐stranded DNA and RNA by mouse and human FTOFEBS Letters, 2008
- Crystal structures of DNA/RNA repair enzymes AlkB and ABH2 bound to dsDNANature, 2008
- Human ABH3 structure and key residues for oxidative demethylation to reverse DNA/RNA damageThe EMBO Journal, 2006
- Systematic identification of abundant A-to-I editing sites in the human transcriptomeNature Biotechnology, 2004