Mutagenicity in
            <i>Escherichia coli</i>
            of the major DNA adduct derived from the endogenous mutagen malondialdehyde

Fink, Stephen P.; Reddy, G. Ramachandra; Marnett, Lawrence J.

doi:10.1073/pnas.94.16.8652

Cited by 161 publications

(188 citation statements)

References 33 publications

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“…The involvement of NER is indicated by both increased mutation frequency and increased adducted-template replication in the NER-deficient strains. Similarly, it was recently shown (84)(85)(86)(87) that E. coli NER is also implicated in repair of the major acrolein-derived DNA adduct, g-HO-PdG (Fig. 3), which has been detected in DNA from healthy human tissues.…”

Section: Repair Of Six-membered Propano-g Derivatives and M 1 G By Thsupporting

confidence: 59%

“…Overlapping repair also exists for some exocyclic adducts, since, chemically, most of the exocyclic adducts are nonbulky, which makes them potential targets for various pathways. For example, both NER and MMR are implicated in repair of PdG and M 1 G, (83,86,91) whereas both BER and NER can act on 1,N 2 -eG. (36,48,72,76) Overlap between glycosylases is also common as examplified by the in vitro identification of the eC-activity in three human DNA glycosylase, TDG, SMUG1 and MBD4.…”

Section: Discussionmentioning

confidence: 99%

“…In 1997, Marnett and co-workers (83,86) reported that both PdG and M 1 G are repaired in vivo by the E. coli UvrABCmediated NER system, with similar efficiencies, based on the mutagenesis assays using M13 genomes containing a single adduct. The involvement of NER is indicated by both increased mutation frequency and increased adducted-template replication in the NER-deficient strains.…”

Section: Repair Of Six-membered Propano-g Derivatives and M 1 G By Thmentioning

confidence: 99%

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Repair of exocyclic DNA adducts: rings of complexity

Hang

2004

BioEssays

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SummaryExocyclic DNA adducts are mutagenic lesions that can be formed by both exogenous and endogenous mutagens/ carcinogens. These adducts are structurally analogs but can differ in certain features such as ring size, conjugation, planarity and substitution. Although the information on the biological role of the repair activities for these adducts is largely unknown, considerable progress has been made on their reaction mechanisms, substrate specificities and kinetic properties that are affected by adduct structures. At least four different mechanisms appear to have evolved for the removal of specific exocyclic adducts. These include base excision repair, nucleotide excision repair, mismatch repair, and AP endonuclease-mediated repair. This overview highlights the recent progress in such areas with emphasis on structure-activity relationships. It is also apparent that more information is needed for a better understanding of the biological and structural implications of exocyclic adducts and their repair.

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Section: Repair Of Six-membered Propano-g Derivatives and M 1 G By Thsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Section: Repair Of Six-membered Propano-g Derivatives and M 1 G By Thmentioning

confidence: 99%

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Repair of exocyclic DNA adducts: rings of complexity

Hang

2004

BioEssays

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“…M 1 dG is mutagenic in bacterial and mammalian cells (13)(14)(15)(16) and can be extracted from the genomic DNA of humans and animals (17)(18)(19). M 1 -dG is reported to be a substrate for the nucleotide excision repair pathway (NER), which accounts for its appearance in human urine (13,20).…”

Section: Introductionmentioning

confidence: 99%

Metabolism in Vitro and in Vivo of the DNA Base Adduct, M₁G

Knutson

Akingbade

Crews

et al. 2007

Chem. Res. Toxicol.

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Oxidative damage is considered a major contributing factor to genetic diseases including cancer. Our laboratory is evaluating endogenously formed DNA adducts as genomic biomarkers of oxidative injury. Recent efforts have focused on investigating the metabolic stability of adducts in vitro and in vivo. Here, we demonstrate that the base adduct, M 1 G, undergoes oxidative metabolism in vitro in rat liver cytosol (RLC, K m ) 105 µM and V max /K m ) 0.005 min -1 mg -1 ) and in vivo when administered intravenously to male Sprague Dawley rats. LC-MS analysis revealed two metabolites containing successive additions of 16 amu. One-and two-dimensional NMR experiments showed that oxidation occurred first at the 6-position of the pyrimido ring, forming 6-oxo-M 1 G, and then at the 2-position of the imidazole ring, yielding 2,6-dioxo-M 1 G. Authentic 6-oxo-M 1 G was chemically synthesized and observed to undergo metabolism to 2,6-dioxo-M 1 G in RLC (K m ) 210 µM and V max /K m ) 0.005 min -1 mg -1 ). Allopurinol partially inhibited M 1 G metabolism (75%) and completely inhibited 6-oxo-M 1 G metabolism in RLC. These inhibition studies suggest that xanthine oxidase is the principal enzyme acting on M 1 G in RLC and the only enzyme that converts 6-oxo-M 1 G to 2,6-dioxo-M 1 G. Both M 1 G and 6-oxo-M 1 G are better substrates (5-fold) for oxidative metabolism in RLC than the deoxynucleoside, M 1 dG. Alternative repair pathways or biological processing of M 1 dG makes the fate of M 1 G of interest as a potential marker of oxidative damage in vivo.

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“…M 1 dG is excised from genomic DNA by nucleotide excision repair (NER) and has been detected in the urine of healthy humans. [3,4] Urinary analysis is a convenient, noninvasive approach for determining adduct burden, making M 1 dG an attractive biomarker for oxidative stress. We recently reported that M 1 dG is a substrate for cellular oxidases and is rapidly converted to 3-(2-deoxy-β-D-erythropentofuranosyl)-3,4-dihydropyrimido[1,2-α]purine-6,10-dione (6-oxo-M 1 dG) after NER excision from DNA (Scheme 1).…”

Section: Introductionmentioning

confidence: 99%