CHAPTER 8: AlkB and Its Homologues – DNA Repair and Beyond

AlkB is an Fe(ii)/2-oxoglutarate-dependent dioxygenase that is part of the adaptive response to alkylating agents in Escherichia coli. AlkB hydroxylates a wide variety of alkylated DNA bases producing unstable intermediates which decompose to restore the non-alkylated bases. Homologues exist in other bacteria, metazoa (e.g. nine in humans), plants and viruses, but not in archaea, with many catalysing the same oxidative demethylation reactions as for AlkB. The mammalian enzymes Alkbh2 and Alkbh3 catalyse direct DNA repair, Alkbh5 and FTO (Alkbh9) are RNA demethylases, and Alkbh8 is used to synthesize a tRNA, while the remaining mammalian homologues have alternative functions. Alkbh1 is an apurinic/apyrimidinic lyase in addition to exhibiting demethylase activities, but no clear role for the Alkbh1 protein has emerged. Alkbh4 is involved in cell division and potentially demethylates actin, whereas the mitochondrial homologue Alkbh7 has a role in obesity; however, no enzymatic activity has been linked to Alkbh4 or Alkbh7. Here, we discuss AlkB as the ‘archetype’ of this class of hydroxylases, compare it to Alkbh2 and Alkbh3, and then briefly review the diverse (and largely unknown) functions of Alkbh1, Alkbh4, Alkbh6 and Alkbh7. Alkbh5, Alkbh8 and Alkbh9 (FTO) are described separately.