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Health Span and Life Span in Transgenic Mice with Modulated DNA Repair
Author(s) -
Walter Christi A.,
Zhou ZiQiang,
Manguino Diwi,
Ikeno Yuji,
Reddick Robert,
Nelson James,
Intano Gabriel,
Herbert Damon C.,
McMahan C. Alex,
Hanes Martha
Publication year - 2001
Publication title -
annals of the new york academy of sciences
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.712
H-Index - 248
eISSN - 1749-6632
pISSN - 0077-8923
DOI - 10.1111/j.1749-6632.2001.tb05643.x
Subject(s) - dna repair , transgene , biology , dna damage , mutagenesis , xrcc1 , hepatocellular carcinoma , genetically modified mouse , gene , microbiology and biotechnology , mutation , dna , genetics , cancer research , genotype , single nucleotide polymorphism
A bstract : One way to better understand the contribution of DNA repair, DNA damage, and mutagenesis in aging would be to enhance DNA repair activity, lower DNA damage, and lower mutagenesis. Because the repair protein O 6 ‐methylguanine‐DNA methyltransferase (MGMT) acts alone and stoichiometrically, the human MGMT (hMGMT) cDNA was selected to test the feasibility of enhancing DNA repair activity in transgenic mice. MGMT activity is largely responsible for ameliorating the deleterious effects of O 6 ‐methylguanine (O 6 mG) lesions in DNA in a direct reversal mechanism. A transgene was constructed consisting of a portion of the human transferrin (TF) promoter and hMGMT cDNA such that hMGMT is expressed in transgenic mouse brain and liver. Expression of hMGMT was associated with a significant reduction in the occurrence of an age‐related hepatocellular carcinoma in male mice at 15 months of age. Longitudinal and cross‐sectional studies were initiated to determine whether the reduced incidence of hepatocellular carcinoma would impact median or maximum life span. The cross‐sectional study performed on 15‐month‐old male animals confirmed the reduced occurrence of spontaneous hepatocellular carcinoma. At 30 months of age, however, the occurrence of hepatocellular carcinoma in at least one transgenic line was similar to that for nontransgenic animals. The longitudinal study is ongoing; however, at present no significant differences in life span have been detected. Tissues expressing the MGMT transgene also displayed greater resistance to alkylation‐induced tumor formation. These results suggest that transgenes can be used to direct enhanced DNA repair gene expression and that enhanced expression can protect animals from certain spontaneous and induced tumors.