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AlkB (Alkylation B) is a protein found in E. coli, induced during an adaptive response and involved in the direct reversal of alkylation damage.[1][2] AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by SN2 type of chemical agents.[3] It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA.[1][4] AlkB is an alpha-ketoglutarate-dependent hydroxylase, a superfamily non-haem iron-containing proteins. It oxidatively demethylates the DNA substrate.[1][4] Demethylation by AlkB is accompanied with release of CO2, succinate, and formaldehyde.[4]

Human homologs

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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.[5]

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.[6][7]

FTO, which is associated with obesity in humans, is the first identified RNA demethylase. It demethylates N6-methyladenosine in mRNA.[8]

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.

Virus homologs

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AlkB domains are present within viral replication-associated proteins of plant RNA viruses of the families Closteroviridae, Alphaflexiviridae, Betaflexiviridae, and Secoviridae.[9] Potyviridae is the largest family of plant RNA viruses;[10] among these the AlkB domain is embedded in P1 proteases of endive necrotic mosaic virus (ENMV) of genus Potyvirus, French endive necrotic mosaic virus (FENMV) of Potyvirus, and blackberry virus Y (BlVY) of Brambyvirus.[11][12]

Functions

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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.[13] 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.[14] 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.[15]

Experimental results show that AlkB domains from plant viruses have RNA demethylase activity in vitro.[16] AlkB homologs from plants show the pro-viral roles, and may participate in plant antiviral immunity by regulating the levels of N6-methyladenosine (m6A), a common type of RNA modification.[11][17][18]

References

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  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. ^ Yu, Bomina; Hunt, John F. (25 August 2009). "Enzymological and structural studies of the mechanism of promiscuous substrate recognition by the oxidative DNA repair enzyme AlkB". Proceedings of the National Academy of Sciences USA. 106 (34): 14315–14320. Bibcode:2009PNAS..10614315Y. doi:10.1073/pnas.0812938106. PMC 2725012. PMID 19706517.
  3. ^ 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.
  4. ^ 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. S2CID 4324333.
  5. ^ 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.
  6. ^ 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.
  7. ^ 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. Bibcode:2011NatCo...2..172V. doi:10.1038/ncomms1173. hdl:10852/74450. PMID 21285950.
  8. ^ 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.
  9. ^ Bratlie, Marit S.; Drabløs, Finn (2005-01-03). "Bioinformatic mapping of AlkB homology domains in viruses". BMC Genomics. 6 (1): 1. doi:10.1186/1471-2164-6-1. ISSN 1471-2164. PMC 544882. PMID 15627404.
  10. ^ Pasin, Fabio; Daròs, José-Antonio; Tzanetakis, Ioannis E. (2022-07-01). "Proteome expansion in the Potyviridae evolutionary radiation". FEMS Microbiology Reviews. 46 (4): fuac011. doi:10.1093/femsre/fuac011. ISSN 1574-6976. PMC 9249622. PMID 35195244.
  11. ^ a b Yue, Jianying; Wei, Yao; Sun, Zhenqi; Chen, Yahan; Wei, Xuefeng; Wang, Haijuan; Pasin, Fabio; Zhao, Mingmin (October 2022). "AlkB RNA demethylase homologues and N6 -methyladenosine are involved in Potyvirus infection". Molecular Plant Pathology. 23 (10): 1555–1564. doi:10.1111/mpp.13239. ISSN 1364-3703. PMC 9452765. PMID 35700092.
  12. ^ Susaimuthu, James; Tzanetakis, Ioannis E.; Gergerich, Rose C.; Martin, Robert R. (February 2008). "A member of a new genus in the Potyviridae infects Rubus". Virus Research. 131 (2): 145–151. doi:10.1016/j.virusres.2007.09.001. PMID 17933412.
  13. ^ 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. Bibcode:2004PNAS..10114051D. doi:10.1073/pnas.0403489101. PMC 521119. PMID 15381779.
  14. ^ Frick; et al. (2007). "Alleviation of 1,N6-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB". PNAS. 104 (3): 755–760. Bibcode:2007PNAS..104..755F. doi:10.1073/pnas.0607377104. PMC 1783386. PMID 17213319.
  15. ^ 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. S2CID 23235920.
  16. ^ van den Born, Erwin; Omelchenko, Marina V.; Bekkelund, Anders; Leihne, Vibeke; Koonin, Eugene V.; Dolja, Valerian V.; Falnes, Pål Ø (October 2008). "Viral AlkB proteins repair RNA damage by oxidative demethylation". Nucleic Acids Research. 36 (17): 5451–5461. doi:10.1093/nar/gkn519. ISSN 1362-4962. PMC 2553587. PMID 18718927.
  17. ^ Martínez-Pérez, Mireya; Aparicio, Frederic; López-Gresa, Maria Pilar; Bellés, Jose María; Sánchez-Navarro, Jesus A.; Pallás, Vicente (2017-10-03). "Arabidopsis m6A demethylase activity modulates viral infection of a plant virus and the m6A abundance in its genomic RNAs". Proceedings of the National Academy of Sciences of the United States of America. 114 (40): 10755–10760. Bibcode:2017PNAS..11410755M. doi:10.1073/pnas.1703139114. ISSN 1091-6490. PMC 5635872. PMID 28923956.
  18. ^ Martínez-Pérez, Mireya; Gómez-Mena, Concepción; Alvarado-Marchena, Luis; Nadi, Riad; Micol, José Luis; Pallas, Vicente; Aparicio, Frederic (2021). "The m6A RNA Demethylase ALKBH9B Plays a Critical Role for Vascular Movement of Alfalfa Mosaic Virus in Arabidopsis". Frontiers in Microbiology. 12: 745576. doi:10.3389/fmicb.2021.745576. ISSN 1664-302X. PMC 8521051. PMID 34671333.
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