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

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 varying over 3-4 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 results 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.

Authors:
Publication Date:
Research Org.:
Lawrence Livermore National Laboratory (LLNL), Livermore, CA (United States)
Sponsoring Org.:
USDOE
OSTI Identifier:
15014200
Report Number(s):
UCRL-JRNL-204188
Journal ID: ISSN 0891-5849; FRBMEH; TRN: US200805%%337
DOE Contract Number:  
W-7405-ENG-48
Resource Type:
Journal Article
Journal Name:
Free Radical Biology and Medicine
Additional Journal Information:
Journal Volume: 37; Journal Issue: 3; Journal ID: ISSN 0891-5849
Country of Publication:
United States
Language:
English
Subject:
99 GENERAL AND MISCELLANEOUS//MATHEMATICS, COMPUTING, AND INFORMATION SCIENCE; 59 BASIC BIOLOGICAL SCIENCES; AGING; BIOLOGY; CAPACITY; DISEASES; DNA; DNA DAMAGES; DNA REPAIR; EXCISION REPAIR; METABOLISM; PRODUCTION; RADICALS

Citation Formats

Sokhansanj, B A, and Wilson, III, D M. Oxidative DNA damage background estimated by a system model of base excision repair. United States: N. p., 2004. Web. doi:10.1016/j.freeradbiomed.2004.05.003.
Sokhansanj, B A, & Wilson, III, D M. Oxidative DNA damage background estimated by a system model of base excision repair. United States. https://doi.org/10.1016/j.freeradbiomed.2004.05.003
Sokhansanj, B A, and Wilson, III, D M. 2004. "Oxidative DNA damage background estimated by a system model of base excision repair". United States. https://doi.org/10.1016/j.freeradbiomed.2004.05.003. https://www.osti.gov/servlets/purl/15014200.
@article{osti_15014200,
title = {Oxidative DNA damage background estimated by a system model of base excision repair},
author = {Sokhansanj, B A and Wilson, III, D M},
abstractNote = {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 varying over 3-4 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 results 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.},
doi = {10.1016/j.freeradbiomed.2004.05.003},
url = {https://www.osti.gov/biblio/15014200}, journal = {Free Radical Biology and Medicine},
issn = {0891-5849},
number = 3,
volume = 37,
place = {United States},
year = {Thu May 13 00:00:00 EDT 2004},
month = {Thu May 13 00:00:00 EDT 2004}
}

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