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

Aamodt, Rolf; Falnes, Pål Ø.; Johansen, Rune; Seeberg, Erling; Bjørås, Magnar

doi:10.1074/jbc.m314277200

Cited by 26 publications

(27 citation statements)

References 37 publications

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“…Another distinct feature of human AAG is that it shows no preference to Oxa-containing base pairs. It has been suggested that AAG evolved from a hypoxanthine-specific DNA glycosylase to a broader substrate enzyme (33,44). The novel ODG activities in mammalian AAG underscore the intriguing adaptation of the active site to all three deaminated purine and several alkylated purine lesions.…”

Section: Resultsmentioning

confidence: 99%

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Hitchcock

Dong

Connor

et al. 2004

Journal of Biological Chemistry

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Oxanine (Oxa) is a deaminated base lesion derived from guanine in which the N 1 -nitrogen is substituted by oxygen. This work reports the mutagenicity of oxanine as well as oxanine DNA glycosylase (ODG) activities in mammalian systems. Using human DNA polymerase ␤, deoxyoxanosine triphosphate is only incorporated opposite cytosine (Cyt). When an oxanine base is in a DNA template, Cyt is efficiently incorporated opposite the template oxanine; however, adenine and thymine are also incorporated opposite Oxa with an efficiency ϳ80% of a Cyt/Oxa (C/O) base pair. Guanine is incorporated opposite Oxa with the least efficiency, 16% compared with cytosine. ODG activity was detected in several mammalian cell extracts. Among the known human DNA glycosylases tested, human alkyladenine glycosylase (AAG) shows ODG activity, whereas hOGG1, hNEIL1, or hNEIL2 did not. ODG activity was detected in spleen cell extracts of wild type age-matched mice, but little activity was observed in that of Aag knock-out mice, confirming that the ODG activity is intrinsic to AAG. Human AAG can excise Oxa from all four Oxa-containing double-stranded base pairs, Cyt/Oxa, Thy/Oxa, Ade/Oxa, and Gua/Oxa, with no preference to base pairing. Surprisingly, AAG can remove Oxa from single-stranded Oxacontaining DNA as well. Indeed, AAG can also remove 1,N 6 -ethenoadenine from single-stranded DNA. This study extends the deaminated base glycosylase activities of AAG to oxanine; thus, AAG is a mammalian enzyme that can act on all three purine deamination bases, hypoxanthine, xanthine, and oxanine.

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Section: Resultsmentioning

confidence: 99%

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Hitchcock

Dong

Connor

et al. 2004

Journal of Biological Chemistry

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“…Aag protects sporulating B. subtilis cells from cytotoxic and genotoxic effects of MMS. In addition to processing HX, Aag also can remove 3-mA and 3-mG from DNA (23). Therefore, we compared the abilities of wild-type and mutant sporangia lacking Aag and/or YwqL to survive treatment with the alkylating agent MMS.…”

Section: Expression Of Aag Is Primarily During Spore Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

“…However, HX can be processed by another repair protein, termed Aag; this alkyl adenine glycosylase is encoded in the genome of B. subtilis by aag (formerly yxlJ), and its product possesses functional and structural similarity with human AAG (23). In addition, a biochemical study indicated that the purified Aag protein preferentially eliminates HX from DNA over alkylated bases (23). In the genome of B. subtilis, aag is oriented adjacent to but in the opposite orientation from katX, a gene expressed only in the developing forespore compartment of sporulating cells and encoding a catalase that protects germinating spores against hydrogen peroxide (24).…”

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confidence: 99%

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Aag Hypoxanthine-DNA Glycosylase Is Synthesized in the Forespore Compartment and Involved in Counteracting the Genotoxic and Mutagenic Effects of Hypoxanthine and Alkylated Bases in DNA during Bacillus subtilis Sporulation

et al. 2016

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Aag from Bacillus subtilis has been implicated in in vitro removal of hypoxanthine and alkylated bases from DNA. The regulation of expression of aag in B. subtilis and the resistance to genotoxic agents and mutagenic properties of an Aag-deficient strain were studied here. A strain with a transcriptional aag-lacZ fusion expressed low levels of ␤-galactosidase during growth and early sporulation but exhibited increased transcription during late stages of this developmental process. Notably, aag-lacZ expression was higher inside the forespore than in the mother cell compartment, and this expression was abolished in a sigG-deficient background, suggesting a forespore-specific mechanism of aag transcription. Two additional findings supported this suggestion: (i) expression of an aag-yfp fusion was observed in the forespore, and (ii) in vivo mapping of the aag transcription start site revealed the existence of upstream regulatory sequences possessing homology to G -dependent promoters. In comparison with the wild-type strain, disruption of aag significantly reduced survival of sporulating B. subtilis cells following nitrous acid or methyl methanesulfonate treatments, and the Rif r mutation frequency was significantly increased in an aag strain. These results suggest that Aag protects the genome of developing B. subtilis sporangia from the cytotoxic and genotoxic effects of base deamination and alkylation. IMPORTANCEIn this study, evidence is presented revealing that aag, encoding a DNA glycosylase implicated in processing of hypoxanthine and alkylated DNA bases, exhibits a forespore-specific pattern of gene expression during B. subtilis sporulation. Consistent with this spatiotemporal mode of expression, Aag was found to protect the sporulating cells of this microorganism from the noxious and mutagenic effects of base deamination and alkylation.T he integrity of genomes of organisms is constantly compromised by intracellular and extracellular factors that have the potential to generate different base modifications, including, oxidations, alkylations, and deaminations (1). These types of nonbulky genetic insults are detected primarily by specific DNA glycosylases and eliminated through the base excision repair (BER) pathway (2). DNA deamination is a major type of spontaneous genetic damage with which cells must contend (3), and the spontaneous loss of the exocyclic amino groups in cytosine, guanine, and adenine yields the bases uracil, xanthine, and hypoxanthine (HX), respectively (4, 5). HX in DNA is potentially mutagenic, since it can pair not only with thymine but also with cytosine and therefore would result in ATto-GC transitions after DNA replication (6). Organisms such as Escherichia coli and Saccharomyces cerevisiae employ the 3-methyladenine DNA glycosylases AlkA and MAG, respectively, to process HX and the modified bases 3-methyladenine, 7-methylguanine, and 7-methyladenine (7,8). Other enzymes of mammalian origin, which are structurally unrelated to E. coli AlkA, include alkyl-adenine-DNA glycosylas...

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“…B. subtilis Aag (yxlJ) is a member of the mammalian AAG family, which is composed of 3-methyladenine DNA glycosylases (1). B. subtilis Aag is able to excise 3-meA and 3-meG but lacks the ability to excise 7-meG in vitro (1). In addition, B. subtilis contains two putative alkyl glycosylases (encoded by yfjP and yhaZ), although their functions and substrate recognition are unknown (193).…”

Section: Methyl and Alkyl Glycosylasesmentioning

confidence: 99%

DNA Repair and Genome Maintenance in Bacillus subtilis

Lenhart

Schroeder

Walsh

et al. 2012

Microbiol Mol Biol Rev

151

155

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SUMMARY From microbes to multicellular eukaryotic organisms, all cells contain pathways responsible for genome maintenance. DNA replication allows for the faithful duplication of the genome, whereas DNA repair pathways preserve DNA integrity in response to damage originating from endogenous and exogenous sources. The basic pathways important for DNA replication and repair are often conserved throughout biology. In bacteria, high-fidelity repair is balanced with low-fidelity repair and mutagenesis. Such a balance is important for maintaining viability while providing an opportunity for the advantageous selection of mutations when faced with a changing environment. Over the last decade, studies of DNA repair pathways in bacteria have demonstrated considerable differences between Gram-positive and Gram-negative organisms. Here we review and discuss the DNA repair, genome maintenance, and DNA damage checkpoint pathways of the Gram-positive bacterium Bacillus subtilis. We present their molecular mechanisms and compare the functions and regulation of several pathways with known information on other organisms. We also discuss DNA repair during different growth phases and the developmental program of sporulation. In summary, we present a review of the function, regulation, and molecular mechanisms of DNA repair and mutagenesis in Gram-positive bacteria, with a strong emphasis on B. subtilis.

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

Cited by 26 publications

References 37 publications

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Oxanine DNA Glycosylase Activity from Mammalian Alkyladenine Glycosylase

Aag Hypoxanthine-DNA Glycosylase Is Synthesized in the Forespore Compartment and Involved in Counteracting the Genotoxic and Mutagenic Effects of Hypoxanthine and Alkylated Bases in DNA during Bacillus subtilis Sporulation

DNA Repair and Genome Maintenance in Bacillus subtilis

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