Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells

Mundt, J. M.; Hah, S. S.; Sumbad, R. A.; Schramm, V.; Henderson, P. T.

doi:10.1093/nar/gkm1032

Incorporation of extracellular 8-oxodG into DNA and RNA requires purine nucleoside phosphorylase in MCF-7 cells

Journal Article · Sun Nov 18 23:00:00 EST 2007 · Nucleic Acids Research

DOI:https://doi.org/10.1093/nar/gkm1032· OSTI ID:1625418

Mundt, J. M. ^[1]; Hah, S. S. ^[2]; Sumbad, R. A. ^[2]; Schramm, V. ^[3]; Henderson, P. T. ^[2]

Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Chemistry, Materials, Earth and Life Sciences Directorate; DOE/OSTI
Lawrence Livermore National Lab. (LLNL), Livermore, CA (United States). Chemistry, Materials, Earth and Life Sciences Directorate
Albert Einstein College of Medicine, Bronx, NY (United States). Dept. of Biochemistry

7,8-Dihydro-8-oxo-2’-deoxyguanosine (8-oxodG) is a well-known marker of oxidative stress. We report a mechanistic analysis of several pathways by which 8-oxodG is converted to nucleotide triphosphates and incorporated into both DNA and RNA. Exposure of MCF-7 cells to [¹⁴C]8-oxodG combined with specific inhibitors of several nucleotide salvage enzymes followed with accelerator mass spectrometry provided precise quantitation of the resulting radiocarbon-labeled species. Concentrations of exogenously dosed nucleobase in RNA reached one per 10⁶ nucleotides, 5–6-fold higher than the maximum observed in DNA. Radiocarbon incorporation into DNA and RNA was abrogated by Immucillin H, an inhibitor of human purine nucleoside phosphorylase (PNP). Inhibition of ribonucleotide reductase (RR) decreased the radiocarbon content of the DNA, but not in RNA, indicating an important role for RR in the formation of 8-oxodG-derived deoxyribonucleotides. Inhibition of deoxycytidine kinase had little effect on radiocarbon incorporation in DNA, which is in contrast to the known ability of mammalian cells to phosphorylate dG. Our data indicate that PNP and RR enable nucleotide salvage of 8-oxodG in MCF-7 cells, a previously unrecognized mechanism that may contribute to mutagenesis and carcinogenesis.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division; National Institutes of Health (NIH); California Breast Cancer Research Program

Grant/Contract Number:: AC52-07NA27344

OSTI ID:: 1625418

Journal Information:: Nucleic Acids Research, Journal Name: Nucleic Acids Research Journal Issue: 1 Vol. 36; ISSN 0305-1048

Publisher:: Oxford University PressCopyright Statement

Country of Publication:: United States

Language:: English

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