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Nucleic Acids Research Advance Access originally published online on November 19, 2007
Nucleic Acids Research 2008 36(1):228-236; doi:10.1093/nar/gkm1032
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Nucleic Acids Research, 2008, Vol. 36, No. 1 228-236
© 2007 The Author(s)
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

Molecular Biology

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

Janna M. Mundt1, Sang Soo Hah1, Rhoda A. Sumbad1, Vern Schramm2 and Paul T. Henderson1,*

1Chemistry, Materials, Earth and Life Sciences Directorate, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA 94551 and 2Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York 10461, USA

*To whom correspondence should be addressed. Tel: +1 925 423 2822; Fax: +1 925 422 2099; Email: henderson48{at}llnl.gov

Received September 9, 2007. Revised October 18, 2007. Accepted October 29, 2007.

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.

The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.


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