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PMID: 10725358 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

Mmh/Ogg1 gene inactivation results in accumulation of 8-hydroxyguanine in mice.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 97 ·No. 8 ·2000-04-11 ·Pages 4156-61

Minowa O, Arai T, Hirano M, Monden Y, Nakai S, Fukuda M, Itoh M, Takano H, Hippou Y, Aburatani H, Masumura K, Nohmi T, Nishimura S, Noda T

Abstract

The major mutagenic base lesion in DNA caused by exposure to reactive oxygen species is 8-hydroxyguanine or 7, 8-dihydro-8-oxoguanine (8-OH-G). Products of the human MMH/OGG1 gene are known to catalyze in vitro the reactions repairing this DNA lesion. To analyze the function of Mmh in vivo, we generated a mouse line carrying a mutant Mmh allele by targeted gene disruption. Mmh homozygous mutant mice were found to have a physically normal appearance, but to have lost nicking activity in liver extracts for substrate DNA containing 8-OH-G, exhibiting a 3-fold increased accumulation of this adduct at 9 weeks of age compared with wild-type or heterozygous mice. Further elevation to 7-fold was observed in 14-week-old animals. Substantial increase of spontaneous mutation frequencies was clearly identified in Mmh mutant mice bearing transgenic gpt genes. These results indicate that exposure of DNA to endogenous oxidative species continuously produces the mutagenic adduct 8-OH-G in mice, and Mmh plays an essential role in repair of this DNA damage.

MeSH Terms
Animals Base Sequence Carbon-Oxygen Lyases/metabolism Chromatography, High Pressure Liquid DNA Primers DNA-(Apurinic or Apyrimidinic Site) Lyase DNA-Formamidopyrimidine Glycosylase Deoxyribonuclease IV (Phage T4-Induced) Electrochemistry Gene Silencing Guanine/analogs & derivatives,metabolism Humans Liver/cytology,enzymology Mice Mice, Transgenic Mutation N-Glycosyl Hydrolases/genetics
Chemicals
DNA Primers 8-hydroxyguanine Guanine Deoxyribonuclease IV (Phage T4-Induced) N-Glycosyl Hydrolases DNA-Formamidopyrimidine Glycosylase Carbon-Oxygen Lyases DNA-(Apurinic or Apyrimidinic Site) Lyase
Authors & Affiliations
14 authors, click to expand affiliations / ORCID
Minowa O
Department of Cell Biology, The Cancer Institute, Japanese Foundation for Cancer Research, 1-37-1 Kami-Ikebukuro, Toshima-Ku, Tokyo 170-8455, Japan.
Arai T
Hirano M
Monden Y
Nakai S
Fukuda M
Itoh M
Takano H
Hippou Y
Aburatani H
Masumura K
Nohmi T
Nishimura S
Noda T
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.050404497
Published
2000-04-11
Pages
4156-61
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC18180
Subset
IM
External Links
PubMed source DOI: 10.1073/pnas.050404497 PMC Full Text View journal details
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