Oxidative DNA damage background estimated by a system model of base excision repair

Free Radical Biology & Medicine
Bahrad A Sokhansanj, David M Wilson

Abstract

Human DNA can be damaged by natural metabolism through free radical production. It has been suggested that the equilibrium between innate damage and cellular DNA repair results in an oxidative DNA damage background that potentially contributes to disease and aging. Efforts to quantitatively characterize the human oxidative DNA damage background level, based on measuring 8-oxoguanine lesions as a biomarker, have led to estimates that vary over three to four orders of magnitude, depending on the method of measurement. We applied a previously developed and validated quantitative pathway model of human DNA base excision repair, integrating experimentally determined endogenous damage rates and model parameters from multiple sources. Our estimates of at most 100 8-oxoguanine lesions per cell are consistent with the low end of data from biochemical and cell biology experiments, a result robust to model limitations and parameter variation. Our findings show the power of quantitative system modeling to interpret composite experimental data and make biologically and physiologically relevant predictions for complex human DNA repair pathway mechanisms and capacity.

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Citations

Apr 15, 2005·Chromosoma·John B Leppard, James J Champoux
Jun 30, 2010·PLoS Computational Biology·Andres KrieteGlenn Booker
Oct 31, 2014·Carcinogenesis·Boris M BrenermanDavid M Wilson
Dec 4, 2010·Proceedings of the National Academy of Sciences of the United States of America·S N KhodyrevaO I Lavrik
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Oct 17, 2012·Journal of Theoretical Biology·Spyros K StamatelosPanos G Georgopoulos
Apr 11, 2018·Radiation Research·Rotem DaudeeEsther Priel

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