Metabolic fate of oxidized guanine ribonucleotides in mammalian cells.
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.
Hayakawa
H
H
Department of Biochemistry, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan. hiroshi@mailserver.med.kyushu-u.ac.jp
Hofer
A
A
Thelander
L
L
Kitajima
S
S
Cai
Y
Y
Oshiro
S
S
Yakushiji
H
H
Nakabeppu
Y
Y
Kuwano
M
M
Sekiguchi
M
M
D000818:Animals; D002417:Cattle; D002478:Cells, Cultured; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000031:analogs & derivatives* / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D019169:Jurkat Cells; D008322:Mammals; D012313:RNA / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism; D012264:Ribonucleotide Reductases / Q000378:metabolism*; D013379:Substrate Specificity; D013552:Swine
D006150:Guanine Nucleotides; C057674:8-hydroxyguanosine triphosphate; C024829:8-hydroxyguanine; D006147:Guanine; D012313:RNA; D006160:Guanosine Triphosphate; D012264:Ribonucleotide Reductases