CHAPTER 9: RNA Demethylation by FTO and ALKBH5

RNA plays a central role in the flow of genetic information in the central dogma. Over 100 structurally distinct post-transcriptional modifications have been identified in RNA, yet little is known about the functions of most of these modifications. N⁶-methyladenosine (m⁶A) is one of the most intriguing RNA modifications and is also the most abundant internal modification in mammalian messenger RNA (mRNA). Here we describe the first two RNA m⁶A demethylases, FTO and ALKBH5, discovered by us. Both belong to the Fe(ii)/2-oxoglutarate-dependent dioxygenases and use an oxidative demethylation mechanism. We review their structures, functions, oxidation mechanisms, as well as biological significance. The emerging field of reversible m⁶A RNA methylation in biological regulation is also discussed.