Different DNA repair strategies to combat the threat from 8-oxoguanine.
Oxidative DNA damage is one of the most common threats to genome stability and DNA repair enzymes provide protection from the effects of oxidized DNA bases. In mammalian cells, base excision repair (BER) mediated by the OGG1 and MYH DNA glycosylases prevents the accumulation of 8-oxoguanine (8-oxoG) in DNA. When steady-state levels of DNA 8-oxoG were measured in myh(-/-) and myh(-/-)/ogg1(-/-) mice, an age-dependent accumulation of the oxidized purine was found in lung and small intestine of doubly defective myh(-/-)/ogg1(-/-) mice. Since there is an increased incidence of lung and small intestinal cancer in myh(-/-)/ogg1(-/-) mice, these findings are consistent with a causal role for unrepaired oxidized DNA bases in cancer development. We previously presented in vitro evidence that mismatch repair (MMR) participates in the repair of oxidative DNA damage and msh2(-/-) mouse embryo fibroblasts also have increased steady state levels of DNA 8-oxoG. To investigate whether DNA 8-oxoG also accumulates in vivo, basal levels were measured in several organs of 4-month-old msh2(-/-) mice and their wild-type counterparts. Msh2(-/-) mice had significantly increased levels of DNA 8-oxoG in spleen, heart, liver, lung, kidney and possibly small intestine but not in bone marrow, thymus or brain. The tissue-specificity of DNA 8-oxoG accumulation in msh2(-/-) and other DNA repair defective mice suggests that DNA protection of different organs is mediated by different combinations of repair pathways.
Russo
Maria Teresa
MT
Department of Environment and Primary Prevention, Istituto Superiore di Sanità, Viale Regina Elena 299, 00161 Rome, Italy.
De Luca
Gabriele
G
Degan
Paolo
P
Bignami
Margherita
M
D000818:Animals; D004249:DNA Damage; D045647:DNA Glycosylases / Q000172:deficiency / Q000235:genetics; D004260:DNA Repair / Q000235:genetics / Q000502:physiology*; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D051718:MutS Homolog 2 Protein / Q000172:deficiency / Q000235:genetics; D010084:Oxidation-Reduction
C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; C485990:Ogg1 protein, mouse; C061738:mutY adenine glycosylase; C497173:Msh2 protein, mouse; D051718:MutS Homolog 2 Protein