Widespread adaptive response against environmental methylating agents in microorganisms

Sedgwick, Barbara; Vaughan, Patrick

doi:10.1016/0027-5107(91)90178-q

Cited by 40 publications

(26 citation statements)

References 72 publications

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“…Moa mutants also lack several other molybdoenzymes, for example, trimethylamine oxide reductase, which reduces trimethylamine oxide to trimethylamine during anaerobic growth (3). Such tertiary amines can be nitrosated; however, the most likely product is dimethylnitrosamine (23), which is not mutagenic in E. coli (41). Thus, it is unclear whether trimethylamine or trimethylamine oxide could be the endogenous precursor of a directly acting mutagenic N-nitroso compound in E. coli.…”

Section: Discussionmentioning

confidence: 99%

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

Taverna¹,

Sedgwick²

1996

J Bacteriol

144

113

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Escherichia coli ada ogt mutants, which are totally deficient in O 6 -methylguanine-DNA methyltransferases, have an increased spontaneous mutation rate. This phenotype is particularly evident in starving cells and suggests the generation of an endogenous DNA alkylating agent under this growth condition. We have found that in wild-type cells, the level of the inducible Ada protein is 20-fold higher in stationary-phase and starving cells than in rapidly growing cells, thus enhancing the defense of these cells against DNA damage. The increased level of Ada in stationary cells is dependent on RpoS, a stationary-phase-specific sigma subunit of RNA polymerase. We have also identified a potential source of the mutagenic agent. Nitrosation of amides and related compounds can generate directly acting methylating agents and can be catalyzed by bacterial enzymes. E. coli moa mutants, which are defective in the synthesis of a molybdopterin cofactor required by several reductases, are deficient in nitrosation activity. It is reported here that a moa mutant shows reduced generation of a mutagenic methylating agent from methylamine (or methylurea) and nitrite added to agar plates. Moreover, a moa mutation eliminates much of the spontaneous mutagenesis in ada ogt mutants. These observations indicate that the major endogenous mutagen is not S-adenosylmethionine but arises by bacterially catalyzed nitrosation.Only a few types of cancer have been attributed to environmental agents. Other carcinogens of primary concern may be transient but highly reactive metabolites that arise during normal metabolism (24, 36). Indeed, several metabolites of amino acids, sugars, oxygen, and lipids are known to be mutagenic. It is, therefore, important to identify metabolites that damage DNA in vivo and result in spontaneous mutagenesis in the absence of adequate DNA repair. For example, reactive oxygen species generated during aerobic metabolism damage DNA bases and sugar residues. Specific oxygen radical detoxification and DNA repair mechanisms prevent or remove this damage (13,14). The increase in the rate of spontaneous mutagenesis in bacteria and yeast mutants that are specifically deficient in the repair of aberrantly methylated DNA bases indicates that methylation of DNA also occurs endogenously (16,34,52,53). Rodent cells may be similarly affected (2).The major mutagenic adduct induced in DNA by methylating agents is O 6 -methylguanine (O 6 -meG). This modified base mispairs with thymine during DNA replication, resulting in GC-to-AT transition mutations. In wild-type cells, O 6 -meG is repaired by ubiquitous O 6 -meG-DNA methyltransferases that directly transfer the methyl group from the modified base to one of their own cysteine residues. As a result of this process, the methyltransferases are inactivated (25). Escherichia coli has two O 6 -meG-DNA methyltransferases, a constitutive Ogt protein and an inducible Ada protein. Each exponentially growing cell contains only two to four molecules of Ada protein and 10-fold more Ogt protein (32,3...

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Section: Discussionmentioning

confidence: 99%

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

Taverna¹,

Sedgwick²

1996

J Bacteriol

144

113

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“…MeCl is probably the most abundant methylating agent in our environment (Crutzen and Andreae, 1990). Chemically, direct acting alkylating agents may be formed by nitrosations, in slightly acidic conditions, of amides, amines, amino acids and peptides (Harrison et al, 1999;Sedgwick, 1997;Sedgwick and Vaughan, 1991). These reactions could possibly occur in decaying matter, in acidic soils or in putrid water.…”

Section: Methylating Agentsmentioning

confidence: 99%

“…The Ada protein also serves as the positive regulator of 'the adaptive response to alkylation damage', which is more concisely named 'the Ada response' by analogy with the SOS, SoxRS and OxyR responses. Various aspects of the Ada response have been the subject of previous detailed reviews (Friedberg et al, 1995;Landini and Volkert, 2000;Lindahl et al, 1988;Samson, 1992;Sedgwick and Vaughan, 1991;Seeberg and Berdal, 1999). Here, we describe the properties of the inducible proteins with particular emphasis on recent findings, such as those from genome sequencing, protein structural studies, analysis of substrate specificities, and the newly discovered function of the AlkB protein.…”

Section: Introductionmentioning

confidence: 99%

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

2002

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“…2 The high number of 3mA DNA glycosylases in Bacillus species probably reflects the heavy exposure of earth bacteria to environmental alkylating agents like methyl chloride. E. coli possesses an inducible repair response to changes in environmental exposure, termed the adaptive response (20,21). The Ada protein, which is a methyltransferase that becomes activated upon methylation exposure, regulates the adaptive response in E. coli and induces transcription of AlkA and other repair proteins involved in protection against alkylation damage.…”

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confidence: 99%

The Bacillus subtilis Counterpart of the Mammalian 3-Methyladenine DNA Glycosylase Has Hypoxanthine and 1,N6-Ethenoadenine as Preferred Substrates

Aamodt

Falnes

Johansen

et al. 2004

Journal of Biological Chemistry

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The AAG family of 3-methyladenine DNA glycosylases was initially thought to be limited to mammalian cells, but genome sequencing efforts have revealed the presence of homologous proteins in certain prokaryotic species as well. Here, we report the first molecular characterization of a functional prokaryotic AAG homologue, i.e. YxlJ, termed bAag, from Bacillus subtilis. The B. subtilis aag gene was expressed in Escherichia coli, and the protein was purified to homogeneity. As expected, B. subtilis Aag was found to be a DNA glycosylase, which releases 3-alkylated purines and hypoxanthine, as well as the cyclic etheno adduct 1,N 6 -ethenoadenine from DNA. However, kinetic analysis showed that bAag removed hypoxanthine much faster than human AAG with a 10-fold higher value for k cat , whereas the rate of excision of 1, N 6 -ethenoadenine was found to be similar. In contrast, it was found that bAag removes 3-methyladenine and 3-methylguanine ϳ10 -20 times more slowly than human AAG, and there was hardly any detectable excision of 7-methylguanine. It thus appears that bAag has a minor role in the repair of DNA alkylation damage and an important role in preventing the mutagenic effects of deaminated purines and cyclic etheno adducts in Bacillus subtilis.Exposure of genomes to a variety of reactive intracellular metabolites and environmental agents results in chemical modifications of the DNA nucleobases, including oxidations, alkylations, and deaminations. Such DNA lesions are primarily repaired through the base excision repair pathway (BER). The first step of BER involves N-glycosylic cleavage of the basesugar bonds by damage-specific DNA glycosylases. The abasic site is cleaved by apurinic/apyrimidinic endonucleases or apurinic/apyrimidinic lyases, and repair is completed through a sequential action of a phosphodiesterase, a DNA polymerase, and a DNA ligase (reviewed in Refs. 1 and 2).Alkylating agents represent one of the most abundant classes of mutagenic and genotoxic agents present in the environment. Repair of alkylation damage is initiated by DNA glycosylases, referred to as 3-methyladenine (3mA) 1 DNA glycosylases, because 3mA is a major substrate for these enzymes.

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Widespread adaptive response against environmental methylating agents in microorganisms

Cited by 40 publications

References 72 publications

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

Generation of an endogenous DNA-methylating agent by nitrosation in Escherichia coli

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

The Bacillus subtilis Counterpart of the Mammalian 3-Methyladenine DNA Glycosylase Has Hypoxanthine and 1,N6-Ethenoadenine as Preferred Substrates

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