Base excision repair (BER) is primarily responsible for removing small, non-helix distorting base lesions from the genome.Small deoxynucleotide (dN) lesions are likely the most widespread type of damage to the DNA. Such lesions result from several chemical processes. Base deamination produces uracil from cytosine; purine dNs are prone to spontaneous hydrolysis of their N-glycosidic bond, resulting in abasic (apurinic/apyrimidinic (AP) sites; oxidation of DNA can lead to formation of many modified nucleobases; and ring nitrogens and exocyclic groups of nucleobases are sites of electrophilic addition. The core base excision repair pathway requires the function of only four proteins: DNA glycosylase, an apurinic/apyrimidinic (AP) endonuclease or AP DNA lyase, a DNA polymerase, and a DNA ligase. The initial step in BER uses DNA glycosylases, which cleave the N-glycosyl bond between the sugar and the base, thus releasing the damaged base to form AP site. In addition to catalyzing the cleavage of N-glycosydic bonds, some glycosylases are bifunctional having an additional AP lyase activity. Processing of the AP site by AP endonuclease or AP lyase resulted in a single-strand break (SSB). Accessory proteins such as poly(ADP-ribose)polymerase-1 (PARP1) and XRCC1 aid in the continuation of the repair process by the recruitment and complexes-forming with repair proteins at the SSBs, and by chromatin modification. DNA polymerase beta (POLB) catalyzed the release of the 5’-terminal deoxyribophosphate (dRP) from the incised AP site. Excision of the damaged base, leaving only a one-nucleotide gap (the appropriate “missing” nucleotide is latter inserted by a DNA polymerase) has been referred to as short-patch (SP)-BER. When the repair patch size is of 2-10 deoxynucleotides it has been referred to as long-patch (LP)-BER). In this case, several enzymes (PCNA, FEN1 and POLB and/or POLD/POLE) act together to remove a blocking terminus that resulted from specific kind of damage to the ribose-phosphates backbone, and to excise and then polymerize a short stretch of nucleotides. The final step of BER entails ligation of the remaining nick, by either LIG1 alone or LIG3–XRCC1 complex. Two additional notes: 1). APEX1 is the main AP endonuclease of the mammalians’ BER. In addition to its central role in BER it has a pleiotropic role in controlling cellular response to oxidative stress, as a transcriptional regulator of various transcription factors or to cell survival or to cell-cycle arrest (NFkB, EGR1, TP53, and HIF1). 2). XPC-RAD26B and Muts-alpha are protein complexes involved the nucleotide excision repair pathway and mismatch repair pathway respectively. It had been shown that these complexes are also involved and promote BER.
