Estimating the effect of human base excision repair protein variants on the repair of oxidative DNA base damage.
Epidemiologic 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 effect 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 variants in many BER proteins and some have been purified and found to exhibit mild kinetic defects. Epidemiologic studies have led to conflicting conclusions on the association between single-nucleotide polymorphism 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 effect 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 nonintuitive consequences of multiple simultaneous variants. Our findings support previous work suggesting that mild BER variants have a minimal effect on pathway capacity whereas more severe defects and simultaneous variation in several BER proteins can lead to inefficient repair and potentially deleterious consequences of cellular damage.
Sokhansanj
Bahrad A
BA
School of Biomedical Engineering, Science and Health Systems, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA. bahrad.sokhansanj@drexel.edu
Wilson
David M
DM
D004249:DNA Damage; D045647:DNA Glycosylases / Q000502:physiology; D011088:DNA Ligases / Q000235:genetics / Q000502:physiology*; D004260:DNA Repair / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D006147:Guanine / Q000031:analogs & derivatives; D006801:Humans; D008433:Mathematics; D008957:Models, Genetic; D017720:Molecular Epidemiology; D009369:Neoplasms / Q000235:genetics*; D011110:Polymorphism, Genetic
C024829:8-hydroxyguanine; D006147:Guanine; D045647:DNA Glycosylases; D011088:DNA Ligases