Error Prone Translesion Synthesis Past γ-Hydroxypropano Deoxyguanosine, the Primary Acrolein-derived Adduct in Mammalian Cells
8-Hydroxy-5,6,7,8-tetrahydropyrimido[1,2- a ]purin- 10(3 H )-one,3-(2â²-deoxyriboside) (1, N 2 -γ-hydroxypropano deoxyguanosine, γ-HOPdG) is a major DNA adduct that forms as a result of exposure to acrolein, an environmental pollutant and a product of endogenous lipid peroxidation. γ-HOPdG has b...
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Veröffentlicht in: | The Journal of biological chemistry 2002-05, Vol.277 (21), p.18257 |
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Hauptverfasser: | , , , , , |
Format: | Artikel |
Sprache: | eng |
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Zusammenfassung: | 8-Hydroxy-5,6,7,8-tetrahydropyrimido[1,2- a ]purin- 10(3 H )-one,3-(2â²-deoxyriboside) (1, N
2 -γ-hydroxypropano deoxyguanosine, γ-HOPdG) is a major DNA adduct that forms as a result of exposure to acrolein, an environmental
pollutant and a product of endogenous lipid peroxidation. γ-HOPdG has been shown previously not to be a miscoding lesion when
replicated in Escherichia coli . In contrast to those prokaryotic studies, in vivo replication and mutagenesis assays in COS-7 cells using single stranded DNA containing a specific γ-HOPdG adduct, revealed
that the γ-HOPdG adduct was significantly mutagenic. Analyses revealed both transversion and transition types of mutations
at an overall mutagenic frequency of 7.4 à 10 â2 /translesion synthesis. In vitro γ-HOPdG strongly blocks DNA synthesis by two major polymerases, pol δ and pol ε. Replicative blockage of pol δ by γ-HOPdG
could be diminished by the addition of proliferating cell nuclear antigen, leading to highly mutagenic translesion bypass
across this adduct. The differential functioning and processing capacities of the mammalian polymerases may be responsible
for the higher mutation frequencies observed in this study when compared with the accurate and efficient nonmutagenic bypass
observed in the bacterial system. |
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ISSN: | 0021-9258 1083-351X |
DOI: | 10.1074/jbc.M112419200 |