Analysis of MTH1 gene function in mice with targeted mutagenesis

Teruhisa Tsuzuki, Akinori Egashira, Shinobu Kura

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Oxidative DNA damage is thought to contribute to carcinogenesis, ageing, and neurological degeneration. Further, the cumulative risk of cancer increases dramatically with age in humans. In general terms, cancer can be regarded as a degenerative disease of ageing. There is evidence for the accumulation of oxidative DNA damage with age based on studies mainly measuring an increase in 8-oxoguanine. 8-Oxo-7,8-dihydro-2′-deoxyguanosine 5′-triphosphate (8-oxo-dGTP) is formed in the nucleotide pool of a cell during normal cellular metabolism. When 8-oxoguanine is incorporated into DNA causes mutation. Organisms possess 8-oxo-dGTPase, an enzyme that specifically degrades 8-oxo-dGTP to 8-oxo-dGMP. To analyze the function of MTH1 with 8-oxo-dGTPase activity in vivo, we generated a mouse line carrying a mutant MTH1 allele created by targeted gene disruption. MTH1 homozygous mutant mice were found to have a physically normal appearance, but seemed to have lost 8-oxo-dGTPase activity in liver extracts. When we examined the susceptibility of the mutant mice to spontaneous tumorigenesis, no significant difference was observed in survival rate of MTH1+/+ and MTH1-/- mice. However, pathological examination revealed a statistically significant difference in the incidence of tumors. More tumors were formed in lungs, livers, and stomachs of MTH1-/- mice than in those of the wild type mice. These studies with MTH1-null mutant mice provided an important insight into the role of this nucleotide sanitization enzyme in terms of the spontaneous tumorigenesis as well as mutagenesis caused by the oxygen-induced DNA damage.

Original languageEnglish
Pages (from-to)71-78
Number of pages8
JournalMutation Research - Fundamental and Molecular Mechanisms of Mutagenesis
Volume477
Issue number1-2
DOIs
Publication statusPublished - Jun 2 2001

Fingerprint

Mutagenesis
Genes
DNA Damage
Carcinogenesis
Neoplasms
Nucleotides
Liver Extracts
Enzymes
Stomach
Alleles
Oxygen
Lung
Mutation
Liver
DNA
Incidence
8-oxodGTPase

All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Health, Toxicology and Mutagenesis

Cite this

Analysis of MTH1 gene function in mice with targeted mutagenesis. / Tsuzuki, Teruhisa; Egashira, Akinori; Kura, Shinobu.

In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis, Vol. 477, No. 1-2, 02.06.2001, p. 71-78.

Research output: Contribution to journalArticle

Tsuzuki, Teruhisa ; Egashira, Akinori ; Kura, Shinobu. / Analysis of MTH1 gene function in mice with targeted mutagenesis. In: Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis. 2001 ; Vol. 477, No. 1-2. pp. 71-78.
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