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National Institute of Environmental Health Sciences

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Your Environment. Your Health.

Publication Detail

Title: In vivo detection and replication studies of α-anomeric lesions of 2'-deoxyribonucleosides.

Authors: Amato, Nicholas J; Zhai, Qianqian; Navarro, Diana C; Niedernhofer, Laura J; Wang, Yinsheng

Published In Nucleic Acids Res, (2015 Sep 30)

Abstract: DNA damage, arising from endogenous metabolism or exposure to environmental agents, may perturb the transmission of genetic information by blocking DNA replication and/or inducing mutations, which contribute to the development of cancer and likely other human diseases. Hydroxyl radical attack on the C1', C3' and C4' of 2-deoxyribose can give rise to epimeric 2-deoxyribose lesions, for which the in vivo occurrence and biological consequences remain largely unexplored. Through independent chemical syntheses of all three epimeric lesions of 2'-deoxyguanosine (dG) and liquid chromatography-tandem mass spectrometry analysis, we demonstrated unambiguously the presence of substantial levels of the α-anomer of dG (α-dG) in calf thymus DNA and in DNA isolated from mouse pancreatic tissues. We further assessed quantitatively the impact of all four α-dN lesions on DNA replication in Escherichia coli by employing a shuttle-vector method. We found that, without SOS induction, all α-dN lesions except α-dA strongly blocked DNA replication and, while replication across α-dA was error-free, replicative bypass of α-dC and α-dG yielded mainly C→A and G→A mutations. In addition, SOS induction could lead to markedly elevated bypass efficiencies for the four α-dN lesions, abolished the G→A mutation for α-dG, pronouncedly reduced the C→A mutation for α-dC and triggered T→A mutation for α-dT. The preferential misincorporation of dTMP opposite the α-dNs could be attributed to the unique base-pairing properties of the nucleobases elicited by the inversion of the configuration of the N-glycosidic linkage. Our results also revealed that Pol V played a major role in bypassing α-dC, α-dG and α-dT in vivo. The abundance of α-dG in mammalian tissue and the impact of the α-dNs on DNA replication demonstrate for the first time the biological significance of this family of DNA lesions.

PubMed ID: 26202973 Exiting the NIEHS site

MeSH Terms: Animals; Base Pairing; DNA Damage*; DNA Replication*; DNA/chemistry; Deoxyguanosine/analysis; Deoxyguanosine/chemistry*; Deoxyribonucleosides/chemistry; Mice; Mutagenesis; Stereoisomerism

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