Investigation of the role of unsaturated aldehydes in the nucleotide excision repair mechanism: implications in Xeroderma Pigmentosum

Abstract

Lipid peroxidation is a crucial redox stress event and has been associated with the development of a number of pathologies such as cancer, neurodegerative and inflammatory diseases. The lipid peroxidation process generates a complex mixture of phospholipid products including hydroperoxides that can decompose leading to electrophilic derivatives as aldehydes and epoxide aldehydes that can react with DNA and proteins (West and Marnett, 2006). Lesions resulting from the reaction of DNA with lipid oxidation products, such as malondialdehyde (MDA), 4-hydroxy-2-nonenal (HNE), 4-oxo-(2E)-nonenal (ONE), 2,4-decadienal (DDE), 4,5-epoxy-(2E)-decenal (EDE), hexenal, acrolein, and crotonaldehyde have been detected as basal levels in human tissues and in clinical situations associated with stress redox disorders (Medeiros, 2009). Interestingly, it has been shown that the intake of dietary polyunsaturated fatty acids correlates with the formation of the 3-(2-deoxy-b-D-erythro-pentofuranosyl) pyrimido[1,2-a]purin-10(3H)-one (M1dGuo) in female leukocytes (Fang et al, 1996). Levels of M1dGuo from 0.004 to 9.15 adducts per 108 nucleotides were reported by Ma et al. (2015) in human leukocyte DNA using a methodology based on LC/nano electrospray ionization high-resolution tandem mass spectrometry (HRMS/MS). Recently, it was demonstrated that a,b-unsaturated aldehydes inhibit Nucleotide Excision Repair (NER) by delaying the recruitment of NER proteins to DNA damage sites. However the mechanisms involved in this process are unknown (Yang and Ibuki, 2017a). In the present project we propose to investigate the molecular mechanisms involved in the a,b-Unsaturated aldehydes delay in NER and the possible consequences in a Xeroderma pigmentosum cell model. The project will have the collaboration of Prof. Nadja C. de Souza-Pinto (IQ-USP). (AU)