APendonuclease

AP endonuclease is an enzyme that cleaves DNA at abasic (apurinic/apyrimidinic) sites, which arise when damaged bases are removed during base excision repair. This incision initiates repair by allowing downstream enzymes to remove the sugar-phosphate moiety and fill the resulting gap with the correct nucleotide.

AP endonucleases are found across all domains of life. In bacteria, several enzymes exhibit AP endonuclease activity, including Endonuclease IV and Exonuclease III, each contributing to processing abasic sites. In humans, the major AP endonuclease is APE1, also known as Ref-1, with additional homologs in other organisms contributing to BER.

Mechanistically, AP endonucleases cleave the phosphodiester backbone on the 5' side of the AP site, producing a 3'-hydroxyl terminus and a 5'-deoxyribose phosphate residue. The 5'-dRP can then be removed by subsequent processing enzymes, such as DNA polymerase beta, to complete gap filling and ligation. AP endonucleases are metal-dependent; APE1 and related enzymes typically require Mg2+ or Mn2+. In addition to their repair function, APE1 has a redox regulatory activity that modulates the DNA-binding ability of several transcription factors, a separate role known as Ref-1.

Biological significance and distribution vary by organism, but AP endonucleases are generally essential for maintaining genome integrity. They localize to the nucleus and, in many cells, mitochondria, contributing to BER in multiple compartments. Defects or altered regulation of AP endonuclease activity can sensitize cells to DNA-damaging agents and have been linked to disease states, including cancer. Because of their central role in DNA repair, AP endonucleases are studied as potential targets for therapeutic intervention, with inhibitors under exploration in cancer treatment.