Molecular Biology of Mutagens and Carcinogens

Singer, Brett C.; Grünberger, Dezider

doi:10.1007/978-1-4613-3772-0

Cited by 599 publications

(206 citation statements)

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“…DNA alkylation occurs due to reactions involving both S N 1 and S N 2 alkylating agents [25], and the susceptibility of each potential alkylation site on the bases or backbone varies on these reagents [2,6,25,26]. AlkB is responsible for repairing the damage caused by the S N 2 type methylating agents such as MMS and methyl halides.…”

Section: E Coli Alkbmentioning

confidence: 99%

“…AlkB is responsible for repairing the damage caused by the S N 2 type methylating agents such as MMS and methyl halides. These can react with single-stranded DNA (ssDNA) to generate large portions of N 1 -methyladenine (1-meA) and N 3 -methylcytosine (3-meC) [2,6,25,26] and they are the main methylation lesions formed [27][28][29]. These methyl adducts could be removed by two chemical mechanisms: (i) a direct displacement of the methyl group by a nucleophilic Cys residue or an activated water, which is similar to the mechanism used by the Ada proteins; or (ii) oxidation of the methyl group to give a hydroxyl intermediate, which decomposes in water to afford the repaired base and formaldehyde.…”

Section: E Coli Alkbmentioning

confidence: 99%

“…The N 1 -position of adenine and N 3 -position of cytosine in most RNAs are exposed in a similar way as they are in ssDNA. In fact, 1-meA and 3-meC occur naturally in transfer RNA in both prokaryotes and eukaryotes [25,77]. Repair of these lesions in RNA is required for correct RNA folding to allow efficient and accurate translation.…”

Section: Repair Of Rna Damagementioning

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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Section: E Coli Alkbmentioning

confidence: 99%

Section: E Coli Alkbmentioning

confidence: 99%

Section: Repair Of Rna Damagementioning

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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“…The glycosylic bond of 3MeA is unstable and readily undergoes spontaneous hydrolysis (2). We measured the rate of spontaneous depurination by treating calf thymus DNA at physiological pH in PBS and quantifying the number of 3MeA lesions remaining in the DNA over time (Fig.…”

Section: In Vivo Repair Of 3mea Lesions In Aag +/+ and Aag -/-Cellsmentioning

confidence: 99%

“…Alkylating agents comprise one of the broadest classes of DNA-damaging agents and DNA alkylation damage can cause teratogenesis and cancer (1,2). Of particular interest are methylated bases, such as 3-methyladenine (3MeA) and , that are formed not only by cancer chemotherapeutics and agents in the environment, but also by endogenous cellular processes (3,4).…”

Section: Introductionmentioning

confidence: 99%

In vivo repair of methylation damage in Aag 3-methyladenine DNA glycosylase null mouse cells

Smith

2000

Nucleic Acids Research

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3-Methyladenine (3MeA) DNA glycosylases initiate base excision repair by removing 3MeA. These glycosylases also remove a broad spectrum of spontaneous and environmentally induced base lesions in vitro. Mouse cells lacking the Aag 3MeA DNA glycosylase (also known as the Mpg, APNG or ANPG DNA glycosylase) are susceptible to 3MeA-induced S phase arrest, chromosome aberrations and apoptosis, but it is not known if Aag is solely responsible for repair of 3MeA in vivo. Here we show that in Aag -/-cells, 3MeA lesions disappear from the genome slightly faster than would be expected by spontaneous depurination alone, suggesting that there may be residual repair of 3MeA. However, repair of 3MeA is at least 10 times slower in Aag -/-cells than in Aag +/+ cells. Consequently, 24 h after exposure to [ 3 H]MNU, 30% of the original 3MeA burden is intact in Aag -/-cells, while 3MeA is undetectable in Aag +/+ cells. Thus, Aag is the major DNA glycosylase for 3MeA repair. We also investigated the in vivo repair kinetics of another Aag substrate, 7-methylguanine. Surprisingly, 7-methylguanine is removed equally efficiently in Aag +/+ and Aag -/-cells, suggesting that another DNA glycosylase acts on lesions previously thought to be repaired by Aag.

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Z-DNA crystallography

Mooers

1997

Biopolymers

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Molecular Biology of Mutagens and Carcinogens

Cited by 599 publications

References 0 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

In vivo repair of methylation damage in Aag 3-methyladenine DNA glycosylase null mouse cells

Z-DNA crystallography

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