Bulky DNA lesions induced by reactive oxygen species

Abstract

The integrity of the human genome is frequently challenged by endogenous and exogenous agents, and reactive oxygen species (ROS) constitute the major endogenous source of DNA damage. ROS-induced single nucleobase lesions have been extensively investigated; however, the formation and biological implications of bulky DNA lesions emanating from ROS exposure remain under-explored. The combination of synthetic organic chemistry and bioanalytical chemistry have led to the discovery of a group of bulky, oxidatively generated DNA lesions. In these lesions, a nucleobase, often a purine base, can be covalently bonded with the 5' carbon of the 2-deoxyribose of the same nucleoside or its neighboring pyrimidine base to give purine cyclonucleosides and nucleobase-nucleobase intrastrand cross-links, respectively. Biochemical studies demonstrated that these lesions could markedly block DNA replication and transcription and that these lesions are repaired by the nucleotide excision repair (NER) pathway. These bulky, oxidatively induced DNA lesions may contribute significantly to neurological disorders that are associated with deficiency in NER and the natural processes of aging.