Repair and mutagenesis at oxidized DNA lesions in the developing brain of wild-type and Ogg1-/- mice.
OGG1 (8-oxoguanine DNA glycosylase-1) is one of the main DNA glycosylases present in mammalian cells. The enzyme removes 7,8-dihydro-8-oxoguanine (8-oxoG) lesions, believed to be the most important oxidized lesions due to their relatively high incidence and their miscoding properties. This study shows that in prenatal mice brains the repair capacity for 8-oxoG is 5-10-fold higher than in adult mice brains. Western blot analysis and repair activity in extracts from Ogg1(-/-) mice revealed that OGG1 was responsible for the efficient 8-oxoG removal from prenatal mice. To investigate how OGG1 protects against oxidative stress-induced mutagenesis, pregnant Big Blue/wild-type and Big Blue/Ogg1(-/-) mice were exposed to nontoxic doses of gamma radiation. A 2.5-fold increase in the mutation frequency in Ogg1(-/-) mouse brains was obtained by exposure to 3.5 Gy at day 19 postfertilization. This was largely due to GC to TA transversions, believed to originate from 8-oxoG mispairing with A during replication. Furthermore, rapid cell divisions seemed to be required for fixation of mutations, as a similar dose of radiation did not increase the mutation frequency, or the frequency of GC to TA transversion, in the adult brain.
Larsen
E
E
Centre for Molecular Biology and Neuroscience and Institute of Medical Microbiology, The National Hospital, University of Oslo, Oslo, Norway. elisabeth.larsen@medisin.uio.no
Reite
K
K
Nesse
G
G
Gran
C
C
Seeberg
E
E
Klungland
A
A
D000818:Animals; D001921:Brain / Q000196:embryology* / Q000378:metabolism / Q000528:radiation effects; D004249:DNA Damage; D045647:DNA Glycosylases / Q000502:physiology*; D004260:DNA Repair; D005260:Female; D005720:Gamma Rays; D006147:Guanine / Q000031:analogs & derivatives / Q000378:metabolism; D006720:Homozygote; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D016296:Mutagenesis / Q000528:radiation effects*; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism
C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; D010100:Oxygen