A quantitative model of human DNA base excision repair. I. Mechanistic insights.
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 Polbeta-mediated BER dominates, with minimal switching to the long-patch subpathway. Sensitivity analysis of the model indicates that the Polbeta-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.
Sokhansanj
Bahrad A
BA
Biology and Biotechnology Research Program, L-441, University of California, Lawrence Livermore National Laboratory, Livermore, CA 94551-9900, USA.
Rodrigue
Garry R
GR
Fitch
J Patrick
JP
Wilson
David M
DM
D004260:DNA Repair; D004259:DNA-Directed DNA Polymerase / Q000032:analysis; D005544:Forecasting; D006801:Humans; D007700:Kinetics; D008957:Models, Genetic; D008962:Models, Theoretical; D012680:Sensitivity and Specificity
D004259:DNA-Directed DNA Polymerase