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  • Methylation of histone tails is important in regulating chro


    Methylation of histone tails is important in regulating 9516 structure and transcription. Methylation occurs at arginine and at mono-, di- or tri-methylated lysine residues. The reversibility of histone methylation was recently revealed by the identification of two histone demethylases, LSD1 and JHDM1A, that utilise different reaction mechanisms [61], [96]. LSD1 is a nuclear flavin-dependent amine oxidase that specifically demethylates mono- and di-methylated H3-lysine4 releasing the methyl groups as formaldehyde [96]. In contrast, JHDM1 is an 2OG-Fe2+-dioxygenase containing a Jumonji C (JmjC) DNA/chromatin-binding domain and demethylates mono- and di-methylated H3-lysine36 [61]. Two other JmjC-dioxygenases were shown more recently to demethylate di- or tri-methylated H3-lysine9 residues [97], [98]. The mammalian JmjC protein family is large and other members may have roles in demethylating different sites of histone modification [99]. Alternatively, the human ABH proteins of unknown function could have such a role. Ada, alkA and alkB are inducible genes of the adaptive response of E. coli to alkylating agents. AidB is the fourth inducible gene of this response [100]. Overexpression of aidB conveys some cellular protection against SN1 methylating agents, such as N-methyl-N′-nitro-N-nitrosoguanidine [101]. AidB has weak homology to acyl-coA oxidases and contains flavine [101], [102]. A proposed role for AidB was in the degradation of endogenous alkylating agents [101] but more recent observations indicated that AidB may bind double-stranded DNA. A molecular model of the AidB homodimer, based on flavo-oxidases of known structure, suggested a positively charged groove that could act as a DNA-binding surface [102]. One possibility is that AidB functions as a demethylase/dealkylase of DNA using a mechanism similar to that of the LSD1 flavo-oxidase in the demethylation of histones [96]. AlkB, ABH2 and ABH3 that are known to repair DNA all have relatively high pIs and positively charged surfaces (Fig. 7 and P.A.B. unpublished data) which could be important in associating with DNA. Consequently, it seems plausible that the high pI of ABH5 and ABH6 indicates a role in nucleotide/nucleic acid repair. The larger human ABH8 protein has a central domain of an AlkB-like demethylase, a short N-terminal region containing a potential recognition motif for binding to RNA or single-stranded DNA (RRM motif) [103] and a distinct C-terminal domain that strongly resembles an S-adenosylmethionine (SAM)-dependent methylase. This open reading frame was first described in Macaca fascicularis (BAB60797) [104], a mouse homolog has now been identified (NP_080579) (Fig. 7) and a partial human sequence is available (AAH15183). The RRM motif suggests that ABH8 may also be a DNA or RNA demethylase. An association of ABH1, 4 and 7 with DNA cannot be predicted, and they could possibly have roles in histone/protein demethylation. ABH7 was reported to be spermatogenesis associated but a role was not suggested (NCBI databases).
    Introduction Genes encoding for isocitrate dehydrogenases 1 and 2, IDH1 and IDH2, are frequently mutated in grade II and grade III anaplastic oligodendrogliomas (AO), mixed oligoastrocytomas and astrocytomas, and WHO grade IV secondary glioblastomas (GBMs) (>75%) (Parsons et al., 2008) as well as several other types of human cancer, including acute myeloid leukemia (AML, 9516 ∼20%), cartilaginous tumors (75%), intrahepatic cholangiocarcinomas (10%–23%), angioimmunoblastic T cell lymphoma (AITLs, ∼20%), and melanoma (∼5%) (reviewed by Cairns and Mak, 2013, Yang et al., 2012). Tumor-derived IDH1 and IDH2 mutations simultaneously cause loss of its normal activity, the production of α-ketoglutarate (α-KG, also known as 2-oxoglutarate), and gain of a neomorphic activity, the reduction of α-KG to D-2-hydroxyglutarate (D-2-HG) (Dang et al., 2009, Yan et al., 2009, Zhao et al., 2009). D-2-HG is structurally similar to α-KG and acts as an antagonist of α-KG to competitively inhibit multiple α-KG-dependent dioxygenases, including the JmjC domain-containing histone demethylases (KDMs) and the TET (ten-eleven translocation) family of DNA hydroxylases (Chowdhury et al., 2011, Xu et al., 2011). Altered epigenetic regulation is currently considered to be a major mechanism whereby IDH mutation and D-2-HG exert their oncogenic effects.