Formation of apurinic/apyrimidinic site in nucleic acids and its DNA-protein cross-links

Abstract

Apurinic/apyrimidinic sites, also called the abasic sites, are the most commonly found lesions in DNA and they are reported to be mutagenic and carcinogenic. Abasic sites can be induced by spontaneous hydrolysis, physical treatments as well as chemical treatments by cleavage of N-glycosidic bonds. After that, there will be loss of nucleobases, forming a ribosyl moiety which is in equilibrium between a ring-closed and a ring-opened structure. Abasic sites are mutagenic and carcinogenic because of the highly reactive carbonyl group in the ring-opened structure. However, if the abasic sites are not being repaired, they are even in greater mutagenic potential and can lead to severe biological consequences. The highly reactive ring-opened form of abasic site can react with biomacromolecules in close proximity to form crosslinks like DNA-DNA intra cross-links and DNA-protein cross-links. Covalently bonded biomacromolecules can interrupt several metabolic processes like DNA replication, recombination and transcription. Without appropriate repair of the cross-links can finally lead to cell apoptosis. The study of the formation of abasic site in both DNA and RNA and its DNA-protein crosslinks are of great importance in understanding related human diseases. The goal of my first project is to apply the developed LC-MS/MS method of high sensitivity and selectivity to quantitate the amount of abasic site from spontaneous hydrolysis as well as to study the formation rate of abasic site in both DNA and RNA under the exposure of chemicals. It is anticipated that the method can be used for assessing the risk of related human diseases. The goal of my second project is to find out a suitable biomarker for the detection of DNA-protein cross-links (DPCs) in biological systems by using LC-MS/MS system. It is anticipated that the biomarker found can be used for the quantitation of DNA-protein cross-links as well as for the study of related human diseases.

Date of Award	2017
Original language	English
Awarding Institution	The Hong Kong University of Science and Technology