DNA Repair and Cancer Therapy: Targeting APE1/Ref-1 Using Dietary Agents

Figure 1

The DNA base excision repair (BER) pathway. DNA glycosylases initiate BER by recognizing and removing DNA damage forming an apurinic/apyrimidinic (AP) site. In MFG-BER, APE1/Ref-1 hydrolyzes the phosphate bond 5′ to the AP site leaving a 3′-OH group and a 5′-deoxyribose phosphate (5′-dRP) termini. DNA polymerase β (β-pol) then excises the 5′-dRP moiety generating a 5′-phosphate (5′-P). If the pathway is initiated by a bifunctional DNA glycosylase, removal of the damaged base and AP site formation is followed by AP lyase activity that hydrolyzes the 3′-bond to the AP site, resulting in a phospho-α,β-unsaturated aldehyde AP site (PUA). APE1/Ref-1 processes this site resulting in a 3′-OH group. BER then proceeds via short-patch or long-patch BER. In short-patch BER, β-pol inserts a single nucleotide in the AP site and LigIIIα ligates the DNA backbone. In long-patch BER, pol δ/ε inserts 2-8 nucleotides in the AP site. The resulting DNA flap is excised by the FEN1/PCNA endonuclease complex and the DNA backbone ligated by Ligase I (LIG1).