Nucleotide Incision Repair: An Alternative and Ubiquitous Pathway to Handle Oxidative DNA Damage

Abstract

Aerobic respiration and exogenous factors such as ionizing radiation and drugs generate reactive oxygen species (ROS). DNA has limited chemical stability and it is one of the most biologically important targets of ROS.1 Oxidative DNA lesions are believed to be a major type of endogenous damage leading to human degenerative disorders including cancer, cardiovascular disease and brain dysfunction. The clinical features of inherited human DNA repair deficiency disorders such as Cockayne syndrome and Fanconi’s anemia point to the complex nature of endogenous oxidative DNA damage which may include bulky adducts, interstrand crosslinks and clustered lesions. Oxidized DNA bases are substrates for two overlapping pathways: base excision repair (BER) and nucleotide incision repair (NIR). In the BER pathway, a DNA glycosylase clealvles the N-glycosylic bond between the modified base and deoxyribose, leaving either an abasic site or a single-strand break in DNA.2 Alternatively, in the NIR pathway, an apurinic/apyrimidinic (AP) endonuclease incises oxidatively damage DNA in a DNA glycosylase-independent manner, providing the correct ends for DNA synthesis, coupled to the repair of the remaining 5′-dangling modified nucleotide.3 We have demonstrated that the major human apurinic/apyrimidinic (AP) endonuclease (Ape1) is involved in the NIR pathway.4 NIR and BER pathways share many common substrates suggesting that they work in concert to cleanse genomic DNA of potentially mutagenic and cytotoxic lesions. Recently, we have genetically separated AP endonuclease and nucleotide incision activities to demonstrate that NIR handles a distinct type of oxidative DNA damage that cannot be processed in the BER pathway.5 The aim of this review is to summarise the present knowledge about the alternative DNA repair pathways for oxidised base modifications.