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AlkB protein is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage.[1] AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by SN2 type of chemical agents.[2] It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA.[1][3] AlkB is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. It oxidatively demethylates the DNA substrate.[1][3] Demethylation by AlkB is accompanied with release of CO2, succinate, and formaldehyde.[3]

Human homologs

There are nine human homologs of AlkB.[1] They are:

ABH3, like E. coli AlkB, is specific for SS DNA and RNA[1] whereas ABH2 has higher affinity for damages in double-stranded DNA.[4]

ALKBH8 has a RNA recognition motif, a methyltransferase domain, and an AlkB-like domain. The methyltransferase domain generates the wobble nucleoside 5-methoxycarbonylmethyluridine (mcm5U) from its precursor 5-carboxymethyluridine (cm5U). The AlkB-like domain generates (S)-5-methoxycarbonylhydroxymethyluridine (mchm5U)in Gly-tRNA-UCC.[5][6]

FTO, which is associated with obesity in humans, is the first identified RNA demethylase. It demethylates N6-methyladenosine in mRNA.[7]

There is also another very different protein called AlkB or alkane hydroxylase. It is the catalytic subunit of a non-heme diiron protein, catalyzing the hydroxylation of alkanes, in aerobic bacteria that are able to utilize alkanes as a carbon source.

Functions

AlkB has since been shown to have an ever expanding range of substrates since its initial discovery by Sedgwick, Lindahl, Seeberg and Falnes. Not only does it remove alkylation damage from the positively charged 1-methyl adenines and 3-methyl cytosines, but also from the neutral bases of 1-methyl guanine and 3-methyl thymine.[8] AlkB has been shown as the first example of a DNA repair enzyme converting one type of DNA damage that blocks DNA replication, to another type of damage that the DNA polymerase can traverse with ease. This was seen for the cyclic lesion ethanoadenine (not to be confused with ethenoadenine...see below), which upon hydroxylation by AlkB, affords an N6-acetaldehyde lesion, thus affording an 'adenine' hydrogen-bonding face.[9] In contrast to the previous types of alkylation damage removed by AlkB via a hydroxylation mechanism, AlkB has been shown to epoxidize the double bond of ethenoadenine, which is hydrolyzed to a diol, and ultimately released as the dialdehyde glyoxal, thus restoring the undamaged adenine in the DNA.[10]

References

  1. ^ a b c d e Errol C.Friedberg, Graham c. Walker, Wolfram Siede, Richard D. Wood, Roger A. schultz, Tom Ellenberger, DNA Repair and Mutagenesis, 2nd Edition, ASM press, ISBN 1-55581-319-4
  2. ^ Dinglay; et al. (2000). "Defective processing of methylated single-stranded DNA by E. coli alkB mutants". Genes Dev. 14 (16): 2097–2105. doi:10.1101/gad.14.16.2097. PMC 316854. PMID 10950872.
  3. ^ a b c Trewick; et al. (2002). "Oxidative demethylation by E. coli alkB directly reverts DNA base damage". Nature. 419 (6903): 174–178. doi:10.1038/nature00908. PMID 12226667.
  4. ^ Jeanette Ringvoll; et al. (2006). "Repair deficient mice reveal mABH2 as the primary oxidative demethylase for repairing 1meA and 3meC lesions in DNA". The EMBO Journal. 25 (10): 2189–2198. doi:10.1038/sj.emboj.7601109. PMC 1462979. PMID 16642038.
  5. ^ Fu, Y; Dai, Q; Zhang, W; Ren, J; Pan, T; He, C (Nov 15, 2010). "The AlkB domain of mammalian ABH8 catalyzes hydroxylation of 5-methoxycarbonylmethyluridine at the wobble position of tRNA". Angewandte Chemie International Edition in English. 49 (47): 8885–8. doi:10.1002/anie.201001242. PMC 3134247. PMID 20583019.
  6. ^ van den Born, Erwin; Vågbø, Cathrine B.; Songe-Møller, Lene; Leihne, Vibeke; Lien, Guro F.; Leszczynska, Grazyna; Malkiewicz, Andrzej; Krokan, Hans E.; Kirpekar, Finn; Klungland, Arne; Falnes, Pål Ø. (1 February 2011). "ALKBH8-mediated formation of a novel diastereomeric pair of wobble nucleosides in mammalian tRNA". Nature Communications. 2: 172. doi:10.1038/ncomms1173. PMID 21285950.
  7. ^ Jia, Guifang; Fu, Ye; Zhao, Xu; Dai, Qing; Zheng, Guanqun; Yang, Ying; Yi, Chengqi; Lindahl, Tomas; Pan, Tao; Yang, Yun-Gui; He, Chuan (16 October 2011). "N6-Methyladenosine in nuclear RNA is a major substrate of the obesity-associated FTO". Nature Chemical Biology. 7 (12): 885–887. doi:10.1038/nchembio.687. PMC 3218240. PMID 22002720.
  8. ^ Delaney; et al. (2004). "Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli". PNAS. 101 (39): 14051–14056. doi:10.1073/pnas.0403489101. PMC 521119. PMID 15381779.
  9. ^ Frick; et al. (2007). "Alleviation of 1,N6-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB". PNAS. 104 (3): 755–760. doi:10.1073/pnas.0607377104. PMC 1783386. PMID 17213319.
  10. ^ Delaney; et al. (2005). "AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo". Nat. Struct. Mol. Biol. 12 (10): 855–860. doi:10.1038/nsmb996. PMID 16200073.
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