Effects of diethylmaleate on DNA damage and repair in the mouse brain.
The enzyme 8-oxoguanine DNA glycosylase 1 participates in the repair of damaged DNA by excising the oxidized base 8-hydroxy-2'-deoxyguanosine. We have previously demonstrated that enzymatic activity of this enzyme is inversely related to the levels of the damaged base in specific brain regions. We now report that the activity of 8-oxoguanine DNA glycosylase 1 is increased in a region-specific manner following treatment with diethylmaleate, a compound that reduces glutathione levels in the cell. A single treatment with diethylmaleate elicited a significant increase ( approximately 2-fold) in the activity of 8-oxoguanine DNA glycosylase 1 in three brain regions with low basal levels of activity (cerebellum, cortex, and pons/medulla). There was no change in the activity of 8-oxoguanine DNA glycosylase 1 in those regions with high basal levels of activity (hippocampus, caudate/putamen, and midbrain). This is the first report to demonstrate that DNA repair capacity can be upregulated in the CNS, and the increased repair activity correlates with a reduction in the levels of DNA damage. The brain region-specific capacity to deal with increased oxidative damage to DNA may be responsible, in part, for the vulnerability of specific neuronal populations with aging, sources of oxidative stress, and neurodegenerative diseases.
Cardozo-Pelaez
Fernando
F
Center for Aging and Brain Repair, Department of Neurology, University of South Florida, Tampa 33612, USA.
Stedeford
Todd J
TJ
Brooks
Phillip J
PJ
Song
Shijie
S
Sánchez-Ramos
Juan R
JR
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D015415:Biomarkers; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D043382:DNA-Formamidopyrimidine Glycosylase; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D005609:Free Radicals / Q000378:metabolism; D005978:Glutathione / Q000378:metabolism; D008297:Male; D008298:Maleates / Q000633:toxicity*; D051379:Mice; D008810:Mice, Inbred C57BL; D009699:N-Glycosyl Hydrolases / Q000378:metabolism; D018384:Oxidative Stress / Q000502:physiology*
D015415:Biomarkers; D005609:Free Radicals; D008298:Maleates; D000080242:8-Hydroxy-2'-Deoxyguanosine; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase; C014476:diethyl maleate; D003849:Deoxyguanosine; D005978:Glutathione