AlkB

AlkB protein is a protein induced during an adaptive response and is involved in the direct reversal of alkylation damage ^[1] . AlkB specifically removes alkylation damage to single stranded (SS) DNA caused by S_N2 type of chemical agents ^[2] . It efficiently removes methyl groups from 1-methyl adenines, 3-methyl cytosines in SS DNA ^[1,3] . AlkB belongs to the Fe (II)/2-oxoglutarate-dependent dioxygenase superfamily and oxidatively demethylates the DNA substrate ^[1,3] . Demethylation by AlkB is accompanied with release of CO₂, succinate and formaldehyde ^[3] .

Human homologs

There are eight human homologs of AlkB, of which, only ABH2 and ABH3 ^[1] have known function. They are:

*, Gene|ALKBH2, Gene|ALKBH3, Gene|ALKBH4, Gene|ALKBH5, Gene|ALKBH6, Gene|ALKBH7, Gene|ALKBH8

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] .

Functions

AlkB has since been shown to have an ever expanding range of substrates since its initial discovery by Sedgwick, Lindahl, and Seeberg. 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 ^[5] . 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 ^[6] . 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 ^[7] .

References

#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
#Dinglay et al (2000) Defective processing of methylated single-stranded DNA by E. coli alkB mutants, Genes Dev 14:2097-2105
#Trewick et al (2002) Oxidative demethylation by E. coli alkB directly reverts DNA base damage, Nature 419:174-178
#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, 25,2189-2198
#Delaney et al (2004) Mutagenesis, genotoxicity, and repair of 1-methyladenine, 3-alkylcytosines, 1-methylguanine, and 3-methylthymine in alkB Escherichia coli, PNAS 101:14051-14056
#Frick et al (2007) Alleviation of 1,N⁶-ethanoadenine genotoxicity by the Escherichia coli adaptive response protein AlkB, PNAS 104:755-760
#Delaney et al (2005) AlkB reverses etheno DNA lesions caused by lipid oxidation in vitro and in vivo, Nat.Struct.Mol.Biol. 12:855-860

External links

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