Aging and defense against generation of 8-oxo-7,8-dihydro-2'-deoxyguanosine in DNA.
The imbalance between the formation of 8-oxo-7,8-dihydro-2'-deoxyguanosine (8-oxodG) in DNA and the efficiency of cellular systems of DNA protection and repair is considered an important factor in the age-dependent development of cancer. This study investigated the relationship between oxidatively damaged DNA and the activity of the DNA repair system and 8-oxo-7,8-dihydro-2'-deoxyguanosine 5'-triphosphate pyrophosphohydrolase (8-oxodGTPase) activity in liver and lung tissue from mice at 10-100 weeks of age. The level of 8-oxodG increased with age, whereas the level of formamidopyrimidine DNA glycosylase sites was unaltered. The enzyme activity toward single oxygen-induced DNA damage and mRNA expression levels of Ercc1, Neil1, and Ogg1 remained unaltered with age. However, the 8-oxodGTPase activity in the liver was 18% (95% CI: 0.2-37%) lower in mice at 25 and 50 weeks than in 10-week-old mice. The 10- and 100-week-old mice had similar 8-oxodGTPase activity. In contrast, the mRNA expression of Nudt1 was statistically unaltered that likely resulted from higher variation of measurements. The accumulation of 8-oxodG with age is not a direct consequence of decreased enzyme activity toward singlet oxygen-induced substrate DNA. An age-related higher level of 8-oxodG even occurs concomitantly with high 8-oxodGTPase activity.
Mikkelsen
Lone
L
Institute of Public Health, University of Copenhagen, Øster Farimagsgade 5, 2-floor, DK-1014 Copenhagen K, Denmark.
Bialkowski
Karol
K
Risom
Lotte
L
Løhr
Mille
M
Loft
Steffen
S
Møller
Peter
P
D000080242:8-Hydroxy-2'-Deoxyguanosine; D000818:Animals; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D004247:DNA / Q000737:chemistry / Q000378:metabolism*; D004249:DNA Damage / Q000502:physiology; D045647:DNA Glycosylases / Q000235:genetics / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D045643:DNA Repair Enzymes / Q000235:genetics / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000378:metabolism; D004720:Endonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D008099:Liver / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism
D004268:DNA-Binding Proteins; D000080242:8-Hydroxy-2'-Deoxyguanosine; D004247:DNA; D004720:Endonucleases; C499360:Ercc1 protein, mouse; D010744:Phosphoric Monoester Hydrolases; D045647:DNA Glycosylases; C481347:Neil1 protein, mouse; C485990:Ogg1 protein, mouse; C078207:8-oxodGTPase; D045643:DNA Repair Enzymes; D003849:Deoxyguanosine