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Early steps in the DNA base excision/single-strand interruption repair pathway in mammalian cells Hegde ML; Hazra TK; Mitra SCell Res 2008[Jan]; 18 (1): 27-47Base excision repair (BER) is an evolutionarily conserved process for maintaining genomic integrity by eliminating several dozen damaged (oxidized or alkylated) or inappropriate bases that are generated endogenously or induced by genotoxicants, predominantly, reactive oxygen species (ROS). BER involves 4-5 steps starting with base excision by a DNA glycosylase, followed by a common pathway usually involving an AP-endonuclease (APE) to generate 3' OH terminus at the damage site, followed by repair synthesis with a DNA polymerase and nick sealing by a DNA ligase. This pathway is also responsible for repairing DNA single-strand breaks with blocked termini directly generated by ROS. Nearly all glycosylases, far fewer than their substrate lesions particularly for oxidized bases, have broad and overlapping substrate range, and could serve as back-up enzymes in vivo. In contrast, mammalian cells encode only one APE, APE1, unlike two APEs in lower organisms. In spite of overall similarity, BER with distinct subpathways in the mammals is more complex than in E. coli. The 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 by the NEIL family glycosylases or by ROS, requires the phosphatase activity of polynucleotide kinase instead of APE1. Different complexes may utilize distinct DNA polymerases and ligases. Mammalian glycosylases have nonconserved extensions at one of the termini, dispensable for enzymatic activity but needed for interaction with other BER and non-BER proteins for complex formation and organelle targeting. The mammalian enzymes are sometimes covalently modified which may affect activity and complex formation. The focus of this review is on the early steps in mammalian BER for oxidized damage.|*DNA Breaks, Single-Stranded[MESH]|Animals[MESH]|Cell Survival/genetics[MESH]|DNA Adducts/metabolism[MESH]|DNA Glycosylases/physiology[MESH]|DNA Methylation[MESH]|DNA Modification Methylases/metabolism[MESH]|DNA Repair Enzymes/metabolism[MESH]|DNA Repair/genetics/*physiology[MESH]|DNA, Mitochondrial/metabolism[MESH]|DNA-(Apurinic or Apyrimidinic Site) Lyase/genetics/metabolism[MESH]|DNA-Binding Proteins/physiology[MESH]|Eukaryotic Cells/metabolism[MESH]|Humans[MESH]|Mammals/genetics[MESH]|Models, Biological[MESH]|Oxidation-Reduction[MESH]|Poly (ADP-Ribose) Polymerase-1[MESH]|Poly(ADP-ribose) Polymerases/physiology[MESH]|Polynucleotide 5'-Hydroxyl-Kinase/metabolism/physiology[MESH]|Protein Binding[MESH]|Signal Transduction/physiology[MESH]|Tumor Suppressor Proteins/metabolism[MESH]|X-ray Repair Cross Complementing Protein 1[MESH] |
