Solution structure of an 11-mer duplex containing the 3,N4-ethenocytosine adduct opposite 2′-deoxycytidine: implications for the recognition of exocyclic lesions by DNA glycosylases

Cullinan, David B.; Johnson, Francis; Santos, Carlos de los

doi:10.1006/jmbi.1999.3490

Cited by 18 publications

(14 citation statements)

References 32 publications

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“…In addition, the base pairing preferences are similar for both the 8-HM-εC and εC-containing oligonucleotides. The latter compound is closely related structurally to 8-HM-εC and it has been established that it is a mutagenic lesion (24)(25)(26)(27)(28)(29). Moreover, by molecular modeling, we showed that little difference exists in the planarity and sugar conformations of the two derivatives in duplex DNA.…”

Section: Introductionmentioning

confidence: 67%

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

Medina

Zhang

et al. 2002

Biochemistry

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Section: Introductionmentioning

confidence: 67%

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

Medina

Zhang

et al. 2002

Biochemistry

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“…Moreover, the specific interaction of both the MUG and ANPG proteins with 1,N 2 -⑀G when present in DNA suggests that these enzymes are similar with respect to the conformation of their active site pockets. This hypothesis is supported by the computer modeling of ⑀C in the active site of ANPG, which reveals a good fit of the ⑀-base into the active site of the enzyme despite its lack of activity (53). Surprisingly, neither hTDG (the human structural homologue of MUG) nor AlkA (the E. coli functional homologue of ANPG) excises or specifically binds 1,N 2 -⑀G when present in DNA (Figs.…”

Section: Discussionmentioning

confidence: 86%

1,N 2-Ethenoguanine, a Mutagenic DNA Adduct, Is a Primary Substrate of Escherichia coliMismatch-specific Uracil-DNA Glycosylase and Human Alkylpurine-DNA-N-Glycosylase

Saparbaev

Langouët

Privezentzev

et al. 2002

Journal of Biological Chemistry

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The promutagenic and genotoxic exocyclic DNA adduct 1,N 2 -ethenoguanine (1,N 2 -⑀G) is a major product formed in DNA exposed to lipid peroxidation-derived aldehydes in vitro. Here, we report that two structurally unrelated proteins, the Escherichia coli mismatchspecific uracil-DNA glycosylase (MUG) and the human alkylpurine-DNA-N-glycosylase (ANPG), can release 1,N 2 -⑀G from defined oligonucleotides containing a single modified base. A comparison of the kinetic constants of the reaction indicates that the MUG protein removes the 1,N 2 -⑀G lesion more efficiently (Additionally, while the nonconserved, N-terminal 73 amino acids of the ANPG protein are not required for activity on 1,N 6 -ethenoadenine, hypoxanthine, or N-methylpurines, we show that they are essential for 1,N 2 -⑀G-DNA glycosylase activity. Both the MUG and ANPG proteins preferentially excise 1,N 2 -⑀G when it is opposite dC; however, unlike MUG, ANPG is unable to excise 1,N 2 -⑀G when it is opposite dG. Using cell-free extracts from genetically modified E. coli and murine embryonic fibroblasts lacking MUG and mANPG activity, respectively, we show that the incision of the 1,N 2 -⑀G-containing duplex oligonucleotide has an absolute requirement for MUG or ANPG. Taken together these observations suggest a possible role for these proteins in counteracting the genotoxic effects of 1,N 2 -⑀G residues in vivo.

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“…Specific binding of ANPG to ⑀C⅐G suggests that the enzyme recognizes ⑀C in the active site pocket; however, in contrast to MUG and hTDG, is not able to excise the adduct. Cullinan et al (53,54) have shown by computer modeling that the ⑀C nucleoside fits neatly into the active site of ANPG. However, these authors proposed that ANPG is not able to extrude the ⑀C residue from duplex DNA.…”

Section: Discussionmentioning

confidence: 99%

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

Gros¹,

Maksimenko

Privezentzev³

et al. 2004

Journal of Biological Chemistry

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Lipid peroxidation generates aldehydes, which react with DNA bases, forming genotoxic exocyclic etheno(⑀)-adducts. E-bases have been implicated in vinyl chlorideinduced carcinogenesis, and increased levels of these DNA lesions formed by endogenous processes are found in human degenerative disorders. E-adducts are repaired by the base excision repair pathway. Here, we report the efficient biological hijacking of the human alkyl-N-purine-DNA glycosylase (ANPG) by 3,N 4 -ethenocytosine (⑀C) when present in DNA. Unlike the ethenopurines, ANPG does not excise, but binds to ⑀C when present in either double-stranded or single-stranded DNA. We developed a direct assay, based on the fluorescence quenching mechanism of molecular beacons, to measure a DNA glycosylase activity. Molecular beacons containing modified residues have been used to demonstrate that the ⑀C⅐ANPG interaction inhibits excision repair both in reconstituted systems and in cultured human cells. Furthermore, we show that the ⑀C⅐ANPG complex blocks primer extension by the Klenow fragment of DNA polymerase I. These results suggest that ⑀C could be more genotoxic than 1,N 6 -ethenoadenine (⑀A) residues in vivo. The proposed model of ANPG-mediated genotoxicity of ⑀C provides a new insight in the molecular basis of lipid peroxidation-induced cell death and genome instability in cancer.

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Solution structure of an 11-mer duplex containing the 3,N4-ethenocytosine adduct opposite 2′-deoxycytidine: implications for the recognition of exocyclic lesions by DNA glycosylases

Cited by 18 publications

References 32 publications

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

1,N 2-Ethenoguanine, a Mutagenic DNA Adduct, Is a Primary Substrate of Escherichia coliMismatch-specific Uracil-DNA Glycosylase and Human Alkylpurine-DNA-N-Glycosylase

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

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Solution structure of an 11-mer duplex containing the 3,N4-ethenocytosine adduct opposite 2′-deoxycytidine: implications for the recognition of exocyclic lesions by DNA glycosylases

Cited by 18 publications

References 32 publications

8-(Hydroxymethyl)-3,N4-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

8-(Hydroxymethyl)-3,N4-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

1,N 2-Ethenoguanine, a Mutagenic DNA Adduct, Is a Primary Substrate of Escherichia coliMismatch-specific Uracil-DNA Glycosylase and Human Alkylpurine-DNA-N-Glycosylase

Hijacking of the Human Alkyl-N-purine-DNA Glycosylase by 3,N4-Ethenocytosine, a Lipid Peroxidation-induced DNA Adduct

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8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases

8-(Hydroxymethyl)-3,N⁴-etheno-C, a Potential Carcinogenic Glycidaldehyde Product, Miscodes In Vitro Using Mammalian DNA Polymerases