Journal article
Estimating the impact of human base excision repair protein variants on the repair of oxidative DNA base damage
Drexel University. School of Biomedical Engineering, Science, and Health Systems. Faculty Research and Publications.
03 Dec 2007
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Epidemiological studies have revealed a complex association between human genetic variance and cancer risk. Quantitative biological modeling based on experimental data can play a critical role in interpreting the impact of genetic variation on biochemical pathways relevant to cancer development and progression. Defects in human DNA base excision repair (BER) proteins can reduce cellular tolerance to oxidative DNA base damage caused by endogenous and exogenous sources, such as exposure to toxins and ionizing radiation. If not repaired, DNA base damage leads to cell dysfunction and mutagenesis, consequently leading to cancer, disease, and aging. Population screens have identified numerous single nucleotide polymorphism (SNP) variants in many BER proteins, and some have been purified and found to exhibit mild kinetic defects. Epidemiological studies have led to conflicting conclusions on the association between SNP variants in BER proteins and cancer risk. Using experimental data for cellular concentration and the kinetics of normal and variant BER proteins, we apply a previously developed and tested human BER pathway model to (i) estimate the impact of mild variants on BER of abasic sites and 8-oxoguanine, a prominent oxidative DNA base modification, (ii) identify ranges of variation associated with substantial BER capacity loss, and (iii) reveal non-intuitive consequences of multiple simultaneous variants. Our findings support previous work suggesting that mild BER variants have a minimal effect on pathway capacity, while more severe defects and simultaneous variation in several BER proteins can lead to inefficient repair and potentially deleterious consequences of cellular damage.
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Details
- Title
- Estimating the impact of human base excision repair protein variants on the repair of oxidative DNA base damage
- Creators
- Bahrad Ali Sokhansanj (Author) - Drexel University (1970-)David Wilson III (Author) - Drexel University (1970-)
- Publication Details
- Drexel University. School of Biomedical Engineering, Science, and Health Systems. Faculty Research and Publications.
- Publisher
- American Association for Cancer Research (AACR)
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Electrical and Computer Engineering; School of Biomedical Engineering, Science, and Health Systems; Drexel University (1970-)
- Web of Science ID
- WOS:000237713200027
- Scopus ID
- 2-s2.0-33744742622
- Other Identifier
- 991014632307304721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Oncology
- Public, Environmental & Occupational Health