The genetic activity of N6-hydroxyadenine and 2-amino-N6-hydroxyadenine in Escherichia coli, Salmonella typhimurium and Saccharomyces cerevisiae

Pavlov, Youri I.; Noskov, Vladimir N.; Lange, E.; Moiseeva, E.V.; Pshenichnov, M. R.; Khromov-Borisov, N. N.

doi:10.1016/0165-1161(91)90343-7

Cited by 45 publications

(22 citation statements)

References 29 publications

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“…Examples of these agents include 6-N-hydroxylaminopurine (HAP), 2-amino-6-hydroxyaminopurine (AHAP), and N 4 -hydroxycytidine. Notably HAP, an adenine analog in which the exocyclic amino group is replaced by a hydroxylamino group, has been found to be a highly effective mutagen in bacteria, yeast, and mammalian cells [3][4][5].…”

Section: Introductionmentioning

confidence: 99%

Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function

Kozmin

Schaaper

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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Lack of molybdenum cofactor (MoCo) in Escherichia coli and related microorganisms was found to cause hypersensitivity to certain N-hydroxylated base analogs, such as HAP (6-Nhydroxylaminopurine). This observation has lead to a previous proposal that E. coli contains a molybdoenzyme capable of detoxifying such N-hydroxylated analogs. Here, we show that, unexpectedly, deletion of all known or putative molybdoenzymes in E. coli failed to reveal any baseanalog sensitivity, suggesting that a novel type of MoCo-dependent activity is involved. Further, we establish that protection against the analogs does not require the common molybdopterin guaninedinucleotide (MGD) form of the cofactor, but instead the guanosine monophosphate (GMP)-free version of MoCo (MPT) is sufficient.

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Section: Introductionmentioning

confidence: 99%

Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function

Kozmin

Schaaper

2007

Mutation Research/Fundamental and Molecular Mechanisms of Mutag

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“…For example, 6-hydroxylaminopurine (N-6-hydroxyadenine) (HAP) and 2-amino-6-hydroxylaminopurine (AHAP) are very powerful mutagens in phage, bacteria, yeast, and eukaryotic cells (42,43), and they have been termed universal mutagens (42). These adenine derivatives are active when provided as bases or, in some organisms, nucleosides, as they are apparently converted efficiently into the corresponding deoxynucleoside triphosphates (dNTPs), which are then incorporated into DNA by DNA polymerase.…”

mentioning

confidence: 99%

Hypersensitivity of Escherichia coli Δ ( uvrB-bio ) Mutants to 6-Hydroxylaminopurine and Other Base Analogs Is Due to a Defect in Molybdenum Cofactor Biosynthesis

et al. 2000

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We have shown previously that Escherichia coli and Salmonella enterica serovar Typhimurium strains carrying a deletion of the uvrB-bio region are hypersensitive to the mutagenic and toxic action of 6-hydroxylaminopurine (HAP) and related base analogs. This sensitivity is not due to the uvrB excision repair defect associated with this deletion because a uvrB point mutation or a uvrA deficiency does not cause hypersensitivity. In the present work, we have investigated which gene(s) within the deleted region may be responsible for this effect. Using independent approaches, we isolated both a point mutation and a transposon insertion in the moeA gene, which is located in the region covered by the deletion, that conferred HAP sensitivity equal to that conferred by the uvrB-bio deletion. The moeAB operon provides one of a large number of genes responsible for biosynthesis of the molybdenum cofactor. Defects in other genes in the same pathway, such as moa or mod, also lead to the same HAP-hypersensitive phenotype. We propose that the molybdenum cofactor is required as a cofactor for an as yet unidentified enzyme (or enzymes) that acts to inactivate HAP and other related compounds.The biological effects of many mutagenic agents are due to DNA base modifications, both in the DNA and the DNA precursor pool. A group of mutagens containing a preformed modified base, often referred to as base analogs (14), have received increasing attention recently. For example, 8-oxoguanine, in the form of 8-oxo-dGTP or 8-oxo-GTP, is a spontaneously arising guanine oxidation product that contributes substantially to the infidelity of DNA replication (13,35,37) or transcription (58). Specialized systems protecting the cell against 8-oxoguanine have been found in organisms from bacteria to humans (for reviews, see references 13 and 37), including the MutT enzyme, which is capable of hydrolyzing 8-oxodGTP, an activity referred to as pool sanitizing (2,35). Other examples of mutagenic precursor pool contaminants are 5-hydroxy-dCTP (12) and 2-hydroxy-dATP (15), both oxidative stress products. The human MutT homolog hMTH1 has strong activity towards 2-hydroxy-dATP, suggesting that it, in addition to 8-oxo-GTP, could be an important threat if not actively removed (15). In addition, base analogs can be useful tools for probing the mechanisms of mutation avoidance during DNA replication, including base-base discrimination by DNA polymerases (51, 54).An important group of base analogs are the N-hydroxy derivatives of adenine and cytidine (see reference 27 for a review). For example, 6-hydroxylaminopurine (N-6-hydroxyadenine) (HAP) and 2-amino-6-hydroxylaminopurine (AHAP) are very powerful mutagens in phage, bacteria, yeast, and eukaryotic cells (42, 43), and they have been termed universal mutagens (42). These adenine derivatives are active when provided as bases or, in some organisms, nucleosides, as they are apparently converted efficiently into the corresponding deoxynucleoside triphosphates (dNTPs), which are then incorporated into DNA by DNA po...

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“…In the one previous publication on YJL055W, Stepchenkova et al (2005) showed that yjl055w∆ strains have modestly elevated sensitivities to the purine-analogue mutagens 6-hydroxylaminopurine (HAP) and 2-amino-6-hydroxylaminopurine (AHA), which function by misincorporation into DNA (Pavlov et al, 1991;de Serres, 1991). Because the levels of Yjl055Wp can affect responses to both pyrimidine and purine analogues, it seemed possible that the slow growth of the yjl055w∆ strain might reflect a link between the pyrimidine and purine pathways.…”

Section: Resultsmentioning

confidence: 99%

Control of 5‐FOA and 5‐FU resistance by Saccharomyces cerevisiae YJL055W

Nishihama

Pringle

2008

Yeast

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In a URA3 /5-FOA-based dosage-suppressor screen, we isolated a plasmid containing the little-characterized ORF YJL055W. Further analysis showed that this gene did not suppress the mutation of interest. Instead, overexpression of Yjl055Wp directly suppressed the non-viability of URA3 + cells in the presence of 5-FOA. Overexpression of Yjl055Wp also suppressed the lethality induced by 5-FU, but deletion of YJL055W had no detectable effect on resistance to either 5-FOA or 5-FU. Based on these observations and a previous report that a yjl055w mutant has increased sensitivity to purine-analogue mutagens, we suggest that Yjl055Wp may function in one of several pathways for the detoxification of base analogues. However, its precise mechanism of action remains unknown.

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The genetic activity of N6-hydroxyadenine and 2-amino-N6-hydroxyadenine in Escherichia coli, Salmonella typhimurium and Saccharomyces cerevisiae

Cited by 45 publications

References 29 publications

Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function

Molybdenum cofactor-dependent resistance to N-hydroxylated base analogs in Escherichia coli is independent of MobA function

Hypersensitivity of Escherichia coli Δ ( uvrB-bio ) Mutants to 6-Hydroxylaminopurine and Other Base Analogs Is Due to a Defect in Molybdenum Cofactor Biosynthesis

Control of 5‐FOA and 5‐FU resistance by Saccharomyces cerevisiae YJL055W

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