DNA base excision repair: A recipe for survival

Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen altered (oxidized, deaminated or alkylated) or inappropriate bases that could be mutagenic. These base lesions are generated endogenously or induced by various genotoxicants, including reactive oxygen species (ROS), reactive nitrogen species (RNS) or alkylating agents. BER involves 4 or 5 steps starting with excision of the lesion base by distinct DNA glycosylases and then a common pathway to repair the resulting abasic (AP) site or its cleavage products. The same process is also used for repair of single-strand breaks generated directly by ROS and radiation. This pathway is usually initiated by an AP-endonuclease (APE) that generates a 3' OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and finally nick sealing by a DNA ligase. Multiple DNA glycosylases, far fewer than the substrate lesions, have usually broad and overlapping substrate range, and could serve as back-up enzymes of one another in vivo. Mammalian cells, surprisingly, encode only one major APE, APE1, unlike two APEs in lower organisms. In spite of the overall similarity, BER in the mammals is more complex than in E. coli. The mammalian glycosylases form complexes with downstream proteins to carry out efficient repair via distinct subpathways one of which, responsible for repair of strand breaks with 3' phosphate termini generated either by the endonuclease VIII like (NEIL) family glycosylases or directly by ROS, requires the phosphatase activity of polynucleotide kinase (PNK) instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have invariably nonconserved extensions at one of the termini, that are involved in modulating their activity, and also in providing the interaction interface for complex formation with other BER and non-BER proteins and in organelle targeting. Polymorphisms in NEILs and 8-oxoguanine-DNA glycosylase (OGG1) have been linked to various cancers, whereas reduced activities of N-methylpurine-DNA glycosylase (MPG) and thymine-DNA glycosylase (TDG) have been linked to adenocarcinoma type of lung cancer. Mutation in MutY homolog (MYH) also has been linked to colorectal cancer of polyposis type. Thus, BER plays an essential role in maintaining genome integrity, disease prevention and survival.