Cell proliferation in liver of Mmh/Ogg1-deficient mice enhances mutation frequency because of the presence of 8-hydroxyguanine in DNA.
The Mmh/Ogg1 gene product maintains the integrity of the genome by removing the damaged base 8-hydroxyguanine (8-OH-G), one of the major DNA lesions generated by reactive oxygen species. Using Ogg1-deficient mice, we sought to establish if cells having high amounts of 8-OH-G have the ability to proliferate and whether the mutation frequency increases after proliferation in vivo. When KBrO(3), a known renal carcinogen, at a dose of 2 grams/liter was administered to Ogg1 mutant mice for 12 weeks, the amount of 8-OH-G in liver DNA from treated Ogg1(-/-) mice increased 26.1 times that of treated Ogg1(+/+) mice. The accumulated 8-OH-G did not decrease 4 weeks after cessation of KBrO(3) treatment. Partial hepatectomy was performed on Ogg1(+/-) and Ogg1(-/-) mice after being treated with KBrO(3) for 12 weeks. The remnant liver from Ogg1(-/-) mice treated with KBrO(3) regenerated to the same extent as nontreated Ogg1(+/-) mice. In addition, 8-OH-G was not repaired during cell proliferation by partial hepatectomy, indicating that there is no replication coupled repair of preexisting 8-OH-G. The mutation frequency after the regeneration of liver from treated Ogg1(-/-) mice showed a 3.5-fold increase compared with before regeneration. This represents a mutation frequency 6.2 times that of normal levels. The proliferation of cells having accumulated amounts of 8-OH-G caused mainly GC-->TA transversions. These results showed that inactivation of the Ogg1 gene leads to a higher risk of cancer because cells with accumulated 8-OH-G still retain the ability to proliferate, leading to an increase in the mutation frequency.
Arai
Tsuyoshi
T
Banyu Tsukuba Research Institute in Collaboration with Merck Research Laboratories, Tsukuba, Ibaraki 300-2611, Japan.
Kelly
Vincent P
VP
Komoro
Kimiyo
K
Minowa
Osamu
O
Noda
Tetsuo
T
Nishimura
Susumu
S
D000818:Animals; D001959:Bromates; D002273:Carcinogens; D002455:Cell Division / Q000235:genetics; D004247:DNA / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D004249:DNA Damage / Q000235:genetics*; D004260:DNA Repair; D043382:DNA-Formamidopyrimidine Glycosylase; D005260:Female; D006147:Guanine / Q000031:analogs & derivatives* / Q000378:metabolism*; D006498:Hepatectomy; D008099:Liver / Q000166:cytology / Q000187:drug effects / Q000201:enzymology / Q000502:physiology*; D008115:Liver Regeneration / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009154:Mutation; D009699:N-Glycosyl Hydrolases / Q000172:deficiency* / Q000235:genetics
D001959:Bromates; D002273:Carcinogens; C019536:potassium bromate; C024829:8-hydroxyguanine; D006147:Guanine; D004247:DNA; D009699:N-Glycosyl Hydrolases; D043382:DNA-Formamidopyrimidine Glycosylase