DNA Base Excision Repair Pathways

Abstract

Base excision DNA repair (BER) prevents mutagenesis or cell death by correcting most of the hydrolytic, oxidative and alkylation DNA lesions that result from reactions with endogenous as well as environmental agents. Two branches of BER carry out the repair process by replacing either a single or multiple nucleotides, respectively. DNA N-glycosylases (11 distinct proteins in human cells) remove many different damaged or inappropriately inserted bases. The DNA glycosylases recognize modified bases and hydrolyze the glycosidic bond to generate abasic (AP) sites, which then enter the central BER pathway. Similarly, abasic lesions formed by nonenzymatic hydrolysis of or oxidative attack on the glycosidic bond are processed by the BER pathway. The abasic sites are usually cleaved by a hydrolytic AP endonuclease. In some cases, the DNA glycosylase may itself also cleave the AP site in a β- or β, δ-elimination reaction; the resulting 3′-abasic product or 3′-phosphate is excised by AP endonuclease or polynucleotide kinase-phosphatase, respectively. DNA synthesis then replaces at least the missing nucleotide. In mammalian cells this repair synthesis is carried out primarily by DNA polymerase β, which then also excises the 5′-abasic residue, and DNA ligase III completes the repair. In some cases, as with the oxidative lesion 2-deoxyribonolactone, excision by the polymerase is not possible, and additional DNA synthesis takes place that may involve the replication polymerases δ or ε. The resulting displaced flap must then be excised by another replication protein, FEN1, before DNA ligase can complete the repair. The single-nucleotide and “long-patch” BER pathways function both in the nucleus and in mitochondria.