Generation and Elimination of 8-Oxo-7, 8-Dihydro-2'-Deoxyguanosine 5'-Triphosphate, A Mutagenic Substrate for DNA Synthesis, in Human Cells

Hiroshi Hayakawa, Michihiko Kuwano, Akinobu Taketomi, Kunihiko Sakumi, Mutsuo Sekiguchi

Research output: Contribution to journalArticle

140 Citations (Scopus)

Abstract

8-Oxo-7, 8-dihydro-2'-deoxyguanosine 5'-triphosphate (8-oxo-dGTP) is a potent mutagenic substrate for DNA synthesis. The present study deals with generation and degradation of 8-oxo-dGTP in the nucleotide pool of human cells. (1) 8-Oxo-dGTP can be generated not only by direct oxidation of dGTP but also by phosphorylation of 8-oxo-dGDP by nucleoside diphosphate kinase. (2) 8-Oxo-dGTP is rapidly degraded to 8-oxo-dGMP by cellular 8-oxo-dGTPase activity. 8-Oxo-dGMP thus produced cannot be rephosphorylated; guanylate kinase, which phosphorylates both GMP and dGMP to the corresponding nucleoside diphosphates, is totally inactive for 8-oxo-dGMP. (3) 8-Oxo-dGMP is further degraded to 8-oxo-deoxyguanosine by a nucleotidase. The enzyme was partially purified from an extract of human Jurkat cells, and the mode of action was elucidated. 8-Oxo-dGMP is the most preferred substrate of the enzyme, and other nucleoside monophosphates are cleaved at significantly lower rates: Km for 8-oxo-dGMP is 10 times lower than that for dGMP, the second best substrate for the enzyme. The enzyme appears to convert 8-oxo-dGMP, which accumulates in the cellular nucleotide pool, to a form readily excretable to the cell exterior.

Original languageEnglish
Pages (from-to)89-95
Number of pages7
JournalBiochemistry
Volume34
Issue number1
DOIs
Publication statusPublished - Jan 1 1995

All Science Journal Classification (ASJC) codes

  • Biochemistry

Fingerprint Dive into the research topics of 'Generation and Elimination of 8-Oxo-7, 8-Dihydro-2'-Deoxyguanosine 5'-Triphosphate, A Mutagenic Substrate for DNA Synthesis, in Human Cells'. Together they form a unique fingerprint.

  • Cite this