DNA Base Excision Repair Pathways

DNA base excision repair (BER) prevents mutagenesis or cell death by correcting most of the hydrolytic, oxidative, and alkylation DNA lesions due to both cellular reactions and environmental agents. Two branches of BER carry out the repair process by replacing one or multiple nucleotides, respectively. DNA N-glycosylases (11 distinct proteins in human cells) remove many different damaged or inappropriately inserted bases. The DNA glycosylases generate abasic (AP) sites then enter the central BER pathway, along with abasic lesions formed by hydrolysis or oxidative attack. These are cleaved by a hydrolytic AP endonuclease. In some cases, the DNA glycosylase may itself also cleave the AP site in a ?-elimination reaction; the resulting 3?-abasic product is also excised by an AP endonuclease. DNA synthesis then replaces at least the missing nucleotide. In mammalian cells, repair synthesis carried out by DNA polymerase ?, 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 involving the replication polymerases ? or ?. The resulting displaced flap must then be excised by another replication protein, FEN1, before ligase I can complete the repair. The single-nucleotide and 'long-patch' BER pathways function both in the nucleus and in mitochondria.