GENERATION AND ELIMINATION OF 8-OXO-7,8-DIHYDRO-2'-DEOXYGUANOSINE 5'-TRIPHOSPHATE, A MUTAGENIC SUBSTRATE FOR DNA-SYNTHESIS, IN HUMAN-CELLS

被引:149
作者
HAYAKAWA, H [1 ]
TAKETOMI, A [1 ]
SAKUMI, K [1 ]
KUWANO, M [1 ]
SEKIGUCHI, M [1 ]
机构
[1] KYUSHU UNIV,MED INST BIOREGULAT,FUKUOKA 812,JAPAN
关键词
D O I
10.1021/bi00001a011
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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: K-m 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.
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页码:89 / 95
页数:7
相关论文
共 38 条
[1]   ENDOGENOUS MUTAGENS AND THE CAUSES OF AGING AND CANCER [J].
AMES, BN ;
GOLD, LS .
MUTATION RESEARCH, 1991, 250 (1-2) :3-16
[2]   ESCHERICHIA-COLI MUTY GENE-PRODUCT IS REQUIRED FOR SPECIFIC A-G-]C.G MISMATCH CORRECTION [J].
AU, KG ;
CABRERA, M ;
MILLER, JH ;
MODRICH, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (23) :9163-9166
[3]   ESCHERICHIA-COLI MUTY GENE ENCODES AN ADENINE GLYCOSYLASE ACTIVE ON G-A MISPAIRS [J].
AU, KG ;
CLARK, S ;
MILLER, JH ;
MODRICH, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (22) :8877-8881
[4]   REPAIR OF 8-HYDROXYGUANINE IN DNA BY MAMMALIAN N-METHYLPURINE-DNA GLYCOSYLASE [J].
BESSHO, T ;
ROY, R ;
YAMAMOTO, K ;
KASAI, H ;
NISHIMURA, S ;
TANO, K ;
MITRA, S .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1993, 90 (19) :8901-8904
[5]   DEFICIENCY OF 8-HYDROXYGUANINE DNA ENDONUCLEASE ACTIVITY AND ACCUMULATION OF THE 8-HYDROXYGUANINE IN MUTATOR MUTANT (MUTM) OF ESCHERICHIA-COLI [J].
BESSHO, T ;
TANO, K ;
KASAI, H ;
NISHIMURA, S .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1992, 188 (01) :372-378
[6]  
BESSHO T, 1993, J BIOL CHEM, V268, P19416
[7]   INTERRELATIONS BETWEEN SUBSTRATE CYCLES AND DENOVO SYNTHESIS OF PYRIMIDINE DEOXYRIBONUCLEOSIDE TRIPHOSPHATES IN 3T6 CELLS [J].
BIANCHI, V ;
PONTIS, E ;
REICHARD, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1986, 83 (04) :986-990
[8]   SUBSTRATE-SPECIFICITY OF THE ESCHERICHIA-COLI FPG PROTEIN (FORMAMIDOPYRIMIDINE DNA GLYCOSYLASE) - EXCISION OF PURINE LESIONS IN DNA PRODUCED BY IONIZING-RADIATION OR PHOTOSENSITIZATION [J].
BOITEUX, S ;
GAJEWSKI, E ;
LAVAL, J ;
DIZDAROGLU, M .
BIOCHEMISTRY, 1992, 31 (01) :106-110
[9]  
BRADFORD MM, 1976, ANAL BIOCHEM, V72, P248, DOI 10.1016/0003-2697(76)90527-3
[10]  
BULLIONS LC, 1994, J BIOL CHEM, V269, P12339