A novel mechanism for preventing mutations caused by oxidation of guanine nucleotides.
MutT-related proteins, including the Escherichia coli MutT and human MutT homologue 1 (MTH1) proteins, degrade 8-oxo- 7,8-dihydrodeoxyguanosine triphosphate (8-oxo-dGTP) to a monophosphate, thereby preventing mutations caused by the misincorporation of 8-oxoguanine into DNA. Here, we report that human cells have another mechanism for cleaning up the nucleotide pool to ensure accurate DNA replication. The human Nudix type 5 (NUDT5) protein hydrolyses 8-oxo-dGDP to monophosphate with a K(m) of 0.77 microM, a value considerably lower than that for ADP sugars, which were originally identified as being substrates of NUDT5. NUDT5 hydrolyses 8-oxo-dGTP only at very low levels, but is able to substitute for MutT when it is defective. When NUDT5 is expressed in E. coli mutT(-) cells, the increased frequency of spontaneous mutations is decreased to normal levels. Considering the enzymatic parameters of MTH1 and NUDT5 for oxidized guanine nucleotides, NUDT5 might have a much greater role than MTH1 in preventing the occurrence of mutations that are caused by the misincorporation of 8-oxoguanine in human cells.
Ishibashi
Toru
T
Department of Biology and Frontier Research Center, Fukuoka Dental College, Fukuoka 814-0193, Japan.
Hayakawa
Hiroshi
H
Sekiguchi
Mutsuo
M
D000595:Amino Acid Sequence; D003001:Cloning, Molecular; D045643:DNA Repair Enzymes / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D018076:DNA, Complementary / Q000737:chemistry / Q000235:genetics; D003848:Deoxyguanine Nucleotides / Q000378:metabolism; D004926:Escherichia coli / Q000235:genetics / Q000378:metabolism; D029968:Escherichia coli Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D006147:Guanine / Q000031:analogs & derivatives* / Q000737:chemistry; D006150:Guanine Nucleotides / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009154:Mutation; D010084:Oxidation-Reduction; D010744:Phosphoric Monoester Hydrolases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D011755:Pyrophosphatases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D016415:Sequence Alignment
C490485:8-oxo-7,8-dihydrodeoxyguanosine diphosphate; D018076:DNA, Complementary; D003848:Deoxyguanine Nucleotides; D029968:Escherichia coli Proteins; D006150:Guanine Nucleotides; C024829:8-hydroxyguanine; D006147:Guanine; D010744:Phosphoric Monoester Hydrolases; C403715:NUDT5 protein, human; D011755:Pyrophosphatases; C052211:mutT protein, E coli; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes