8-Oxoguanine DNA glycosylase-1-driven DNA base excision repair

Abstract

Purpose of review To provide both an overview and evidence of the potential etiology of oxidative DNA base damage and repair-signaling in chronic inflammation and histological changes associated with asthma. Recent findings Asthma is initiated/maintained by immunological, genetic/epigenetic and environmental factors. It is a world-wide health problem, as current therapies suppress symptoms rather than prevent/reverse the disease, largely due to gaps in understanding its molecular mechanisms. Inflammation, oxidative stress and DNA damage are inseparable phenomena, but their molecular roles in asthma pathogenesis are unclear. It was found that among oxidatively modified DNA bases, 8-oxoguanine (8-oxoG) is one of the most abundant, and its levels in DNA and body fluids are considered a biomarker of ongoing asthmatic processes. Free 8-oxoG forms a complex with 8-oxoguanine DNA glycosylase-1 (OGG1) and activates RAS-family GTPases that induce gene expression to mobilize innate and adaptive immune systems, along with genes regulating airway hyperplasia, hyper-responsiveness and lung remodeling in atopic and non-atopic asthma. Summary DNA’s integrity must be maintained to prevent mutation, so its continuous repair and downstream signaling “fuels” chronic inflammatory processes in asthma, and forms the basic mechanism whose elucidation will allow the development of new drug targets for the prevention/reversal of lung diseases.

8-Oxoguanine DNA glycosylase1–driven DNA repair—A paradoxical role in lung aging

“…We have chosen lungs as it forms a barrier between environment and vertebrate organisms and its decreased function impacts entire health e.g., correlates with poorer cardiovascular performance, cognitive activities and increased subcortical atrophy, and dementia in humans (Carvalhaes-Neto et al, 1995; Janssens, 2005). In addition, environmental pollutants, osmotic, mechanical stress, and oxidative burst by immune cells in airways leads to 8-oxoG formation, consequently OGG1-BER rev in (Ba et al, 2014; Ba et al, 2015; Bacsi et al, 2016; Radak and Boldogh, 2010). Challenge of lungs with 8-oxoG base robustly increases in GTP-bound levels of KRAS but not activation of HRAS or NRAS in line with previous observations (Aguilera-Aguirre et al, 2014).…”

“…Estimates on the absolute numbers of genomic 8-oxoG lesions in airways (nasal, bonchial, bronchiolar epithelium, or subepihelial lung tissues) which directly interact with the environment is not available; however, the levels of the OGG1-BER repair products (e.g., 8-oxoG base) in serum or urine correlates well with dose and length of exposure, chemical composition, and physical nature of the inhaled environmental agents (Ba et al, 2014; Ba et al, 2015). Moreover, an increase free 8-oxoG levels in sputum and bronchoalveolar lavage fluid after environmental exposures (Ba et al, 2014; Bacsi et al, 2016; Proklou et al, 2013).…”

“…Moreover, an increase free 8-oxoG levels in sputum and bronchoalveolar lavage fluid after environmental exposures (Ba et al, 2014; Bacsi et al, 2016; Proklou et al, 2013). In experimental animal models of lung diseases or in age-associated human lung pathologies (e.g., COPD, emphysema, and asthma) showed that one of the most referenced DNA base damage(s) is 8-oxoG (Ba et al, 2014; Ba et al, 2015; Deslee et al, 2009; Igishi et al, 2003). …”

Small Molecule Inhibitors of 8-Oxoguanine DNA Glycosylase-1 (OGG1)

“…In addition to considering OGG1 as a target of small molecule inhibition to augment chemo- and radiotherapeutic strategies, a series of insightful studies have revealed the role of OGG1 in the control of airway inflammation as typified in asthma pathogenesis (reviewed in ref 31). Investigations of the modulation of pulmonary inflammation in Ogg1 −/− and knocked down mice have been reported using ovalbumin or ragweed pollen extract as pro-inflammatory challenges.…”

Affect of Early Life Oxygen Exposure on Proper Lung Development and Response to Respiratory Viral Infections

“…IL-13 is a Th2 cytokine that, when overexpressed in the lung, results in oxidative damage to peripheral blood cells (161). Of note is that oxidized guanidine perpetuates the inflammatory response (162). A related inflammatory mechanism could be present with complexes of oxidized high-mobility group box protein 1, which has been shown to induce hyperoxia-mediated lung inflammation (136,163).…”