8-oxo-7,8-dihydroguanine (8-oxoG), often used as a marker of oxidative stress, is generated in nucleic acids by environmental and endogenous reactive oxygen species (ROS). It is a premutagenic lesion in DNA because of its mispairing potential with adenine during replication. The base 8-oxoG is removed from the DNA by 8-oxoG DNA glycosylase 1 (OGG1) in the DNA base excision repair (BER) pathway. Decreased repair and resulting accumulation of 8-oxoG have been related to various human diseases and aging, although its etiological role is poorly understood. Inflammation is the root of most diseases including those of the respiratory, cardiovascular, central nervous systems and of carcinogenesis. Ragweed pollen extract (RWPE: has pro-oxidant and antigenic components) increases the 8-oxoG level in the genome and OGG1 activity in the mouse airways. Downregulation of OGG1 (but not of other oxidized-base specific DNA glycosylases) in the lungs of sensitized mice before RWPE exposure significantly decreased allergic airway inflammation. Importantly, EG8-oxoG (extragenomic 8-oxoG) alone induced chemokine expression in mouse lungs, along with neutrophil accumulation. Our data also show that EG8-oxoG increased the levels of 1) activated small GTPases;2) Ras to Raf-1 binding;and phosphorylation of 3) MEK1,2;4) ERK1,2;and 5) RelA-Ser276. EG8-oxoG induced luciferase expression driven from the CXCL-8 promoter. Notably, other oxidized purine bases had no such effects. These unexpected observations led us to hypothesize that 8-oxoG liberated from DNA by OGG1 functions as a signaling molecule by virtue of its ability to increase levels of activated small GTPases, thereby initiating cascades of cellular activation events leading to increased pro-inflammatory mediator expression and exacerbation of inflammation. We will test this hypothesis by pursuing three Specific Aims. We will investigate whether:
Aim 1) deficiency in 8-oxoG repair renders mice refractory to inflammation;
Aim 2) OGG1's glycosylase activity is post-translationally modulated for release of EG8-oxoG from DNA;
and Aim 3) EG8-oxoG enhances expression of pro-inflammatory mediators via NF-?B, activated by the Ras-Raf-MEK/ERK- MSK1 pathway. A mouse disease model for lung inflammation will be used to establish the etiological relevance of our results generated in cultured cells. Completion of these aims will provide the first evidence that EG8-oxoG is the link between oxidative stress- mediated DNA damage/repair and cellular responses, by acting as a signaling molecule inducing pro- inflammatory chemokine expression. Our mechanistic studies should also lay the foundation for novel therapeutic approaches. For example, drugs that trap, scavenge, or convert EG8-oxoG into a non-signaling form should be beneficial for the prevention of inflammatory processes not only in airways, but also in cardiovascular, and central nervous systems or in obesity-associated inflammatory diseases, among others.
Respiratory diseases affect >eight hundred million people worldwide, and in the US there are approximately twenty million outpatient visits, two million emergency room visits, and half million hospitalization per year related to these diseases. Our novel observations linking oxidative genome damage repair to inflammation and subsequently identifying its molecular mechanism provide an opportunity to explore unconventional preventive therapeutic approaches to inhibit inflammation and thereby subsequent pathogenesis.
|Belanger, KarryAnne K; Ameredes, Bill T; Boldogh, Istvan et al. (2016) The Potential Role of 8-Oxoguanine DNA Glycosylase-Driven DNA Base Excision Repair in Exercise-Induced Asthma. Mediators Inflamm 2016:3762561|
|Hosoki, Koa; Itazawa, Toshiko; Boldogh, Istvan et al. (2016) Neutrophil recruitment by allergens contribute to allergic sensitization and allergic inflammation. Curr Opin Allergy Clin Immunol 16:45-50|
|German, Peter; Saenz, David; Szaniszlo, Peter et al. (2016) 8-Oxoguanine DNA glycosylase1-driven DNA repair-A paradoxical role in lung aging. Mech Ageing Dev :|
|Hosoki, Koa; Aguilera-Aguirre, Leopoldo; Brasier, Allan R et al. (2016) Facilitation of Allergic Sensitization and Allergic Airway Inflammation by Pollen-Induced Innate Neutrophil Recruitment. Am J Respir Cell Mol Biol 54:81-90|
|Bacsi, Attila; Pan, Lang; Ba, Xueqing et al. (2016) Pathophysiology of bronchoconstriction: role of oxidatively damaged DNA repair. Curr Opin Allergy Clin Immunol 16:59-67|
|Wang, Haibo; Dharmalingam, Prakash; Vasquez, Velmarini et al. (2016) Chronic oxidative damage together with genome repair deficiency in the neurons is a double whammy for neurodegeneration: Is damage response signaling a potential therapeutic target? Mech Ageing Dev :|
|Hosoki, Koa; Boldogh, Istvan; Aguilera-Aguirre, Leopoldo et al. (2016) Myeloid differentiation protein 2 facilitates pollen- and cat dander-induced innate and allergic airway inflammation. J Allergy Clin Immunol 137:1506-1513.e2|
|Hosoki, Koa; Boldogh, Istvan; Sur, Sanjiv (2015) Innate responses to pollen allergens. Curr Opin Allergy Clin Immunol 15:79-88|
|Vlahopoulos, Spiros A; Cen, Osman; Hengen, Nina et al. (2015) Dynamic aberrant NF-ÎºB spurs tumorigenesis: a new model encompassing the microenvironment. Cytokine Growth Factor Rev 26:389-403|
|Aguilera-Aguirre, Leopoldo; Hosoki, Koa; Bacsi, Attila et al. (2015) Whole transcriptome analysis reveals an 8-oxoguanine DNA glycosylase-1-driven DNA repair-dependent gene expression linked to essential biological processes. Free Radic Biol Med 81:107-18|
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