Metabolic fate of oxidized guanine ribonucleotides in mammalian cells

Hiroshi Hayakawa, Anders Hofer, Lars Thelander, Shigetaka Kitajima, Yong Cai, Satoru Oshiro, Hiroyuki Yakushiji, Yusaku Nakabeppu, Michihiko Kuwano, Mutsuo Sekiguchi

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112 Citations (Scopus)

Abstract

8-Oxo-7,8-dihydroguanine- (8-oxoguanine-) containing nucleotides are generated in the cellular nucleotide pool by the action of oxygen radicals produced during normal cellular metabolism. We examined the interconversion and metabolic fate of 8-oxoguanine-containing ribonucleotides in mammalian cells. (1) 8-OxoGTP can be generated not only by direct oxidation of GTP but also by phosphorylation of 8-oxoGDP by nucleotide diphosphate kinase, and the 8-oxoGTP thus formed can serve as a substrate for RNA polymerase II to induce transcription errors. (2) MTH1 protein carrying intrinsic 8-oxo-dGTPase activity has the potential to hydrolyze 8-oxoGTP to 8-oxoGMP, thus preventing misincorporation of 8-oxoguanine into RNA. 8-OxoGMP, the degradation product, cannot be reutilized, since guanylate kinase, which has the potential to phosphorylate both GMP and dGMP, is inactive on 8-oxoGMP. (3) Ribonucleotide reductase, which catalyzes reduction of four naturally occurring ribonucleoside diphosphates, cannot convert 8-oxoguanine-containing ribonucleotide to the deoxyribonucleotide. This step appears to serve as a gatekeeper to prevent formation of mutagenic substrates for DNA synthesis from oxidized ribonucleotides.

Original languageEnglish
Pages (from-to)3610-3614
Number of pages5
JournalBiochemistry
Volume38
Issue number12
DOIs
Publication statusPublished - Mar 23 1999

All Science Journal Classification (ASJC) codes

  • Biochemistry

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  • Cite this

    Hayakawa, H., Hofer, A., Thelander, L., Kitajima, S., Cai, Y., Oshiro, S., Yakushiji, H., Nakabeppu, Y., Kuwano, M., & Sekiguchi, M. (1999). Metabolic fate of oxidized guanine ribonucleotides in mammalian cells. Biochemistry, 38(12), 3610-3614. https://doi.org/10.1021/bi982361l