Repair of 3-methylthymine and 1-methylguanine lesions by bacterial and human AlkB proteins

Falnes, Pål Ø.

doi:10.1093/nar/gkh964

Cited by 101 publications

(105 citation statements)

References 36 publications

(71 reference statements)

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“…The mononuclear Fe II center of AlkB with bound αKG has been confirmed both with the overexpression and isolation of the native protein directly from E. coli [41] and by the addition of excess Fe II and αKG to apo-AlkB [30][31][32]38,[42][43][44][45][46]. Studies of the metal center has lead to an observation of an UV-vis band at 560 nm for the native protein [41].…”

Section: The Mononuclear Iron Centermentioning

confidence: 89%

“…These lesions, too, were found to be repaired by AlkB [46]. Furthermore, methylations on the N 3 -position of thymine (3-meT) as well as the N 1 -position of guanine (1-meG) are also repaired by AlkB [32,42,61]. Human homologs ABH2 and ABH3 are able to 3-meT is a minor product when ssDNA or dsDNA is treated with both S N 2 (MMS and dimethylsulfate, DMS) and S N 1 (methylnitrosourea, MNU) agents at neutral pH, constituting up to 0.8% of the total alkylated products.…”

Section: Substratesmentioning

confidence: 99%

Section: Substratesmentioning

confidence: 99%

“…At physiological pH, 3-meT is more slowly repaired than the major lesion found in ssDNA, 3-meC. 1-meG is a major lesion generated when tRNA is treated with MeI but is also repaired slowly compared to 1-meA or 3-meC [42]. The 3-meC and 1-meA are drawn as positively charged in solution; however, they could also exist as the neutral 6-imino (for 1-meA) or 4-imino (for 3-meC) forms, respectively, after isomerization and release of one proton from the exocyclic amino groups [62,63].…”

Section: Substratesmentioning

confidence: 99%

“…AlkB and its human homolog ABH3 were found to effectively repair 1-meA and 3-meC lesions on RNA, a potentially important defense function for cells against alkylation damage [38,77]. AlkB, ABH2 and ABH3 are all able to demethylate 3meT and 1-meG lesions introduced by chemical methylation on tRNA as well [32,42,61]. This unique feature of the AlkB proteins suggests that these proteins may also play important roles in viruses, where RNA encodes genetic information.…”

mentioning

confidence: 99%

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Oxidative dealkylation DNA repair mediated by the mononuclear non-heme iron AlkB proteins

Mishina

2006

Journal of Inorganic Biochemistry

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DNA can be damaged by various intracellular and environmental alkylating agents to produce alkylation base lesions. These base damages, if not repaired promptly, may cause genetic changes that lead to diseases such as cancer. Recently, it was discovered that some of the alkylation DNA base damage can be directly removed by a family of proteins called the AlkB proteins that utilize a mononuclear non-heme iron(II) and α-ketoglutarate as cofactor and cosubstrate. These proteins activate dioxygen and perform an unprecedented oxidative deal-kylation of the alkyl adducts on DNA heteroatoms. This review summarizes the discovery of this activity and the recent research advances in studying this unique DNA repair pathway. The focus is placed on the chemical mechanism and function of these proteins. KeywordsDNA repair; AlkB; ABH; Direct repair; Mononuclear non-heme iron; Dioxygenase; Oxidative dealkylation; Demethylation Direct repair of alkylation DNA damageCellular DNA is subject to nonenzymatic alkylation (methylation) by environmental or chemical mutagens, resulting in adducts that are toxic and mutagenic [1][2][3][4][5][6]. Organisms have evolved a variety of mechanisms to repair these mutagenic damages. Escherichia coli (E. coli) responds to this threat by activating an adaptive responsive pathway, mediated by the E. coli Ada protein [7]. Upon receiving a methyl group from the damaged DNA, Ada turns into a transcriptional activator and activates its own expression and that of the alkB gene and two other genes, alkA and aidB ( Fig. 1(a)) [4,7,8]. The upregulated Ada is a bifunctional protein, which uses a N-terminal Cys38 residue to remove a methyl group fromS p -methylphosphotriester and a C-terminal Cys321 residue to remove a methyl adduct from O 6 -methylguanaine ( Fig. 1(b)) [9][10][11]. Both repair functions are irreversible and represent rare examples of direct repair of DNA damage. AlkA is a glycosylase that cleaves methylated bases from DNA and performs the first step of the well-known base excision repair of base lesions [12][13][14]. The precise function of AidB is still unknown. The function of the last member of this adaptive response, AlkB, also remained unknown until recently despite extensive research efforts. E. coli AlkBSince the first genetic study in 1983 isolating the E. coli mutant with specific sensitivity to the alkylating agent methylmethane sulfonate, MMS [15], the activity of AlkB was undisclosed The Fe II /αKG-dependent dioxygenase superfamily is widespread from bacteria to humans [19] and is the largest known non-heme iron protein family [20][21][22][23]. It represents a wide diversity of enzymes that catalyze the hydroxylation of unactivated C-H groups of a variety of substrates by coupling reductive activation of dioxygen with a decarbox-ylation of αKG, the co-substrate, to succinate. In the event of oxidation one of the oxygen atoms from O 2 is incorporated into the succinate and the other as a hydroxyl in the product [24]. This group of enzymes is known for their importance in ...

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