ALKBHs-facilitated RNA modifications and de-modifications.

The AlkB gene that protects E.coli against methylation damage to DNA was identified more than 3 decades ago. 20 years later, the AlkB protein was shown to catalyze repair of methylated DNA base lesions by oxidative demethylation. Two human AlkB homologs were characterized with similar DNA repair activities and seven additional human AlkB homologs were identified based on sequence homology. All these dioxygenases, ALKBH1-8 and FTO, contain a conserved α-ketoglutarate/iron-dependent domain for methyl modifications and de-modifications. Well-designed research over the last 10 years has identified unforeseen substrate heterogeneity for the AlkB homologs, including novel reversible methyl modifications in RNA. The discoveries of RNA demethylation catalyzed by AlkB family enzymes initiated a new realm of gene expression regulation, although the understanding of precise endogenous activities and roles of these RNA demethylases are still undeveloped. It is worth mentioning that the AlkB mechanism and use of α-ketoglutarate have also emerged to be essential for many enzymes in epigenetic reprogramming that modify and de-modify methylated bases in DNA and methylated amino acids in histones.