Recent progress on the Ada response for inducible repair of DNA alkylation damage

Sedgwick, Barbara; Lindahl, Tomas

doi:10.1038/sj.onc.1205998

Cited by 125 publications

(107 citation statements)

References 70 publications

(59 reference statements)

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“…Cellular 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.…”

Section: Direct Repair Of Alkylation Dna Damagementioning

confidence: 99%

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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Section: Direct Repair Of Alkylation Dna Damagementioning

confidence: 99%

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

Mishina

2006

Journal of Inorganic Biochemistry

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“…Excellent reviews and articles have been written on these subjects in the past; due to space constraints, we apologize for any references that we may have omitted. 3,9,16,[51][52][53] We hope to emphasize the chemical aspects of these repair functions and focus on the recent advances made toward understanding the structure, function, and mechanism of these proteins. Inhibition of human AGT (hAGT) as a potential strategy to improve the efficacy of anticancer alkylation chemotherapies will be discussed, as well as recent strategies to utilize this protein for in vivo imaging and protein-immobilization applications.…”

Section: Scope Of Reviewmentioning

confidence: 99%

“…3,9,16,17,[54][55][56] This so-called adaptive response has been studied extensively in E. coli, in which expression of four genes, ada, alkA, alkB, and aidB is activated through a post-translational modification of the Ada protein. 57 The three gene products, Ada, AlkA, and AlkB, are all engaged in repair of DNA alkylation damage; the function of AidB is still unknown.…”

Section: The Ada-regulated Adaptive Response In E Colimentioning

confidence: 99%

Direct Reversal of DNA Alkylation Damage

Mishina

Duguid

2006

ChemInform

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“…However, both these methylated bases are efficiently removed from DNA by alkyladenine DNA-glycosylase (Scharer and Jiricny 2001), and the resulting abasic sites are repaired by the BER pathway (Seeberg et al 1995), without causing undue cytotoxicity at low concentrations. Interestingly, the cytotoxicity of the above methylating agents is ascribed to 6Me G, detoxified by methylguanine methyl transferase (MGMT), which reverts it back to guanine (Sedgwick and Lindahl 2002). 6Me G residues were implicated in cell killing when cells expressing high levels of MGMT were shown to be highly resistant to killing by MNU (Karran 2001), but how can persistent 6Me G residues in DNA lead to cell death?…”

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confidence: 99%

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

Stojic¹,

Mojas²,

Ćejka³

et al. 2004

Genes Dev.

208

256

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S N 1-type alkylating agents represent an important class of chemotherapeutics, but the molecular mechanisms underlying their cytotoxicity are unknown. Thus, although these substances modify predominantly purine nitrogen atoms, their toxicity appears to result from the processing of O 6 -methylguanine ( 6Me G)-containing mispairs by the mismatch repair (MMR) system, because cells with defective MMR are highly resistant to killing by these agents. In an attempt to understand the role of the MMR system in the molecular transactions underlying the toxicity of alkylating agents, we studied the response of human MMR-proficient and MMR-deficient cells to low concentrations of the prototypic methylating agent N-methyl-N -nitro-N-nitrosoguanidine (MNNG). We now show that MNNG treatment induced a cell cycle arrest that was absolutely dependent on functional MMR. Unusually, the cells arrested only in the second G 2 phase after treatment. Downstream targets of both ATM (Ataxia telangiectasia mutated) and ATR (ATM and Rad3-related) kinases were modified, but only the ablation of ATR, or the inhibition of CHK1, attenuated the arrest. The checkpoint activation was accompanied by the formation of nuclear foci containing the signaling and repair proteins ATR, the S*/T*Q substrate, ␥-H2AX, and replication protein A (RPA). The persistence of these foci implied that they may represent sites of irreparable damage.

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Recent progress on the Ada response for inducible repair of DNA alkylation damage

Cited by 125 publications

References 70 publications

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

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

Direct Reversal of DNA Alkylation Damage

Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase

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Recent progress on the Ada response for inducible repair of DNA alkylation damage

Cited by 125 publications

References 70 publications

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

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

Direct Reversal of DNA Alkylation Damage

Mismatch repair-dependent G2 checkpoint induced by low doses of SN1 type methylating agents requires the ATR kinase

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Mismatch repair-dependent G₂ checkpoint induced by low doses of S_N1 type methylating agents requires the ATR kinase