Nucleic Acids Research, 2002, Vol. 30, No. 8 1817-1825
© 2002 Oxford University Press
A quantitative model of human DNA base excision repair. I. mechanistic insights
1Biology and Biotechnology Research Program, L-441, University of California, Lawrence Livermore National Laboratory, 7000 East Avenue, Livermore, CA 94551-9900, USA, 2Department of Applied Science, College of Engineering, University of California, Davis, Davis, CA 95616-8524, USA and 3Department of Radiation Oncology, University of California Davis Cancer Center, Sacramento, CA 95817, USA
Base excision repair (BER) is a multistep process involving the sequential activity of several proteins that cope with spontaneous and environmentally induced mutagenic and cytotoxic DNA damage. Quantitative kinetic data on single proteins of BER have been used here to develop a mathematical model of the BER pathway. This model was then employed to evaluate mechanistic issues and to determine the sensitivity of pathway throughput to altered enzyme kinetics. Notably, the model predicts considerably less pathway throughput than observed in experimental in vitro assays. This finding, in combination with the effects of pathway cooperativity on model throughput, supports the hypothesis of cooperation during abasic site repair and between the apurinic/apyrimidinic (AP) endonuclease, Ape1, and the 8-oxoguanine DNA glycosylase, Ogg1. The quantitative model also predicts that for 8-oxoguanine and hydrolytic AP site damage, short-patch Polß-mediated BER dominates, with minimal switching to the long-patch subpathway. Sensitivity analysis of the model indicates that the Polß-catalyzed reactions have the most control over pathway throughput, although other BER reactions contribute to pathway efficiency as well. The studies within represent a first step in a developing effort to create a predictive model for BER cellular capacity.
* To whom correspondence should be addressed at present address: Laboratory of Molecular Gerontology, National Institute on Aging, 5600 Nathan Shock Drive, Baltimore, MD 21224-6825, USA. Tel: +1 410 558 8162; Fax: +1 410 558 8157; Email: wilsonda{at}grc.nia.nih.gov
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