Tetracycline-dependent regulation of formamidopyrimidine DNA glycosylase in transgenic mice conditionally reduces oxidative DNA damage in vivo.
8-Oxo-deoxyguanosine (8-oxo-dG) is a pervasive oxidative DNA lesion formed by endogenous oxidative stress and enhanced by drugs and environmental chemicals. This lesion results in transcriptional errors and mutations and is linked to neurodegeneration, teratogenesis, cancer, and other pathologies. We demonstrate that the neonatal central nervous system of transgenic mice carrying the tetracycline-regulable DNA repair gene formamidopyrimidine DNA glycosylase (fpg) has a 50% reduction in 8-oxo-dG levels. This enhanced DNA repair is suppressed by treatment with doxycycline. For the first time, this murine model permits the level of a specific DNA oxidation product to be regulated in a temporally and spatially specific manner, allowing its role as a primary or secondary factor in neurodegenerative disease to be determined in vivo.
Laposa
Rebecca R
RR
Faculty of Pharmacy, University of Toronto, 19 Russell St., Toronto, Ontario, Canada M5S 2S2.
Henderson
Jeffrey T
JT
Wells
Peter G
PG
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000199:Actins / Q000235:genetics; D000818:Animals; D016466:CHO Cells; D002460:Cell Line; D002540:Cerebral Cortex / Q000378:metabolism; D006224:Cricetinae; D004249:DNA Damage; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism*; D004318:Doxycycline / Q000494:pharmacology; D005786:Gene Expression Regulation; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D009699:N-Glycosyl Hydrolases / Q000235:genetics* / Q000378:metabolism; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D020218:Response Elements; D013752:Tetracycline / Q000494:pharmacology*
D000199:Actins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; D013752:Tetracycline; D003849:Deoxyguanosine; D004318:Doxycycline