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.
|Luo, Jixian; Hosoki, Koa; Bacsi, Attila et al. (2014) 8-Oxoguanine DNA glycosylase-1-mediated DNA repair is associated with Rho GTPase activation and ?-smooth muscle actin polymerization. Free Radic Biol Med 73:430-8|
|Ba, Xueqing; Aguilera-Aguirre, Leopoldo; Rashid, Qura Tul Ain Nmi et al. (2014) The role of 8-oxoguanine DNA glycosylase-1 in inflammation. Int J Mol Sci 15:16975-97|
|Aguilera-Aguirre, Leopoldo; Bacsi, Attila; Radak, Zsolt et al. (2014) Innate inflammation induced by the 8-oxoguanine DNA glycosylase-1-KRAS-NF-?B pathway. J Immunol 193:4643-53|
|Ba, Xueqing; Bacsi, Attila; Luo, Jixian et al. (2014) 8-oxoguanine DNA glycosylase-1 augments proinflammatory gene expression by facilitating the recruitment of site-specific transcription factors. J Immunol 192:2384-94|
|Fang, Ling; Choudhary, Sanjeev; Zhao, Yingxin et al. (2014) ATM regulates NF-?B-dependent immediate-early genes via RelA Ser 276 phosphorylation coupled to CDK9 promoter recruitment. Nucleic Acids Res 42:8416-32|
|Hegde, Muralidhar L; Hegde, Pavana M; Bellot, Larry J et al. (2013) Prereplicative repair of oxidized bases in the human genome is mediated by NEIL1 DNA glycosylase together with replication proteins. Proc Natl Acad Sci U S A 110:E3090-9|
|Sarga, L; Hart, N; Koch, L G et al. (2013) Aerobic endurance capacity affects spatial memory and SIRT1 is a potent modulator of 8-oxoguanine repair. Neuroscience 252:326-36|
|Bacsi, Attila; Aguilera-Aguirre, Leopoldo; Szczesny, Bartosz et al. (2013) Down-regulation of 8-oxoguanine DNA glycosylase 1 expression in the airway epithelium ameliorates allergic lung inflammation. DNA Repair (Amst) 12:18-26|
|German, Peter; Szaniszlo, Peter; Hajas, Gyorgy et al. (2013) Activation of cellular signaling by 8-oxoguanine DNA glycosylase-1-initiated DNA base excision repair. DNA Repair (Amst) 12:856-63|
|Hajas, Gyorgy; Bacsi, Attila; Aguilera-Aguirre, Leopoldo et al. (2013) 8-Oxoguanine DNA glycosylase-1 links DNA repair to cellular signaling via the activation of the small GTPase Rac1. Free Radic Biol Med 61:384-94|
Showing the most recent 10 out of 19 publications