title: Deficiencies in mouse Myh and Ogg1 result in tumor predisposition and G to T mutations in codon 12 of the K-ras oncogene in lung tumors.
abstract: Oxidative DNA damage is unavoidably and continuously generated by oxidant byproducts of normal cellular metabolism. The DNA damage repair genes, mutY and mutM, prevent G to T mutations caused by reactive oxygen species in Escherichia coli, but it has remained debatable whether deficiencies in their mammalian counterparts, Myh and Ogg1, are directly involved in tumorigenesis. Here, we demonstrate that deficiencies in Myh and Ogg1 predispose 65.7% of mice to tumors, predominantly lung and ovarian tumors, and lymphomas. Remarkably, subsequent analyses identified G to T mutations in 75% of the lung tumors at an activating hot spot, codon 12, of the K-ras oncogene, but none in their adjacent normal tissues. Moreover, malignant lung tumors were increased with combined heterozygosity of Msh2, a mismatch repair gene involved in oxidative DNA damage repair as well. Thus, oxidative DNA damage appears to play a causal role in tumorigenesis, and codon 12 of K-ras is likely to be an important downstream target in lung tumorigenesis. The multiple oxidative repair genes are required to prevent mutagenesis and tumor formation. The mice described here provide a valuable model for studying the mechanisms of oxidative DNA damage in tumorigenesis and investigating preventive or therapeutic approaches.
authors.affiliation: Department of Microbiology, Immunology, and Molecular Genetics and the Molecular Biology Institute, University of California at Los Angeles, Los Angeles, California, USA.
authors.forename: Yali
authors.initials: Y
authors.lastname: Xie
authors.forename: Hanjing
authors.initials: H
authors.lastname: Yang
authors.forename: Cristina
authors.initials: C
authors.lastname: Cunanan
authors.forename: Kimberly
authors.initials: K
authors.lastname: Okamoto
authors.forename: Darryl
authors.initials: D
authors.lastname: Shibata
authors.forename: Janet
authors.initials: J
authors.lastname: Pan
authors.forename: Deborah E
authors.initials: DE
authors.lastname: Barnes
authors.forename: Tomas
authors.initials: T
authors.lastname: Lindahl
authors.forename: Michael
authors.initials: M
authors.lastname: McIlhatton
authors.forename: Richard
authors.initials: R
authors.lastname: Fishel
authors.forename: Jeffrey H
authors.initials: JH
authors.lastname: Miller
mesh_terms: D000818:Animals; D003062:Codon / Q000235:genetics; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency* / Q000235:genetics; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D011905:Genes, ras / Q000235:genetics*; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000473:pathology; D008223:Lymphoma / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein; D010051:Ovarian Neoplasms / Q000235:genetics; D010084:Oxidation-Reduction; D017354:Point Mutation; D011518:Proto-Oncogene Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D003062:Codon; D004268:DNA-Binding Proteins; D011518:Proto-Oncogene Proteins; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase; C497172:MSH2 protein, human; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein