Carcinogenesis, Vol. 23, No. 9, 1419-1425,
September 2002
© 2002 Oxford University Press
CANCER BIOLOGY |
Induction of DNA polymerase ß-dependent base excision repair in response to oxidative stress in vivo
1 Department of Nutrition and Food Science, 3009 Science Hall, Wayne State University, Detroit, MI 48202, USA and
2 Department of Physiology, University of Texas Health Science Center at San Antonio, TX 78284, USA
Base excision repair (BER) is the DNA repair pathway primarily responsible for repairing small base modifications and abasic sites caused by normal cellular metabolism or environmental insult. Strong evidence supports the requirement of DNA polymerase ß (ß-pol) in the BER pathway involving single nucleotide gap filling DNA synthesis in mammalian systems. In this study, we examine the relationship between oxidative stress, cellular levels of ß-pol and BER to determine whether oxidizing agents can upregulate BER capacity in vivo. Intraperitoneal injection of 2-nitropropane (2-NP, 100 mg/kg), an oxidative stress-inducing agent, in C57BL/6 mice was found to generate 8-hydroxydeoxyguanosine (8-OHdG) in liver tissue (4-fold increase, P < 0.001). We also observed a 4–5-fold increase in levels of DNA single strand breaks in 2-NP treated animals. The protein level of the tumor suppressor gene, p53 was also induced in liver by 2-NP (2.1-fold, P < 0.01), indicating an induction of DNA damage. In addition, we observed a 2–3-fold increase in mutant frequency in the lacI gene after exposure to 2-NP. Interestingly, an increase in DNA damage upregulated the level of ß-pol as well as BER capacity (42%, P < 0.05). These results suggest that ß-pol and BER can be upregulated in response to oxidative stress in vivo. Furthermore, data show that heterozygous ß-pol knockout (ß-pol+/–) mice express higher levels of p53 in response to 2-NP as compared with wild-type littermates. While the knockout and wild-type mice display similar levels of 8-OHdG after 2-NP exposure, the ß-pol+/– mice exhibit a significant increase in DNA single strand breaks. These findings suggest that in mice, a reduction in ß-pol expression results in a higher accumulation of DNA damage by 2-NP, thus establishing the importance of the ß-pol-dependent BER pathway in repairing oxidative damage.
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