Molecular mechanisms of DNA Repair

Our cells are continuously exposed to DNA-damaging agents, including what we eat and drink, the air we breathe, exposure to the sun, as well as DNA-damaging cancer treatments. In the case of DNA-damaging cancer treatments, the goal is for the DNA damage to selectively kill cancer cells without being inhibited by the cells DNA repair mechanisms. However, in other cases, you need to enhance DNA repair to prevent cancer-causing mutations. Thus, by researching DNA repair, we hope to develop therapeutic strategies to selectively enhance or reduce DNA repair depending on a patient’s need.

Oxidative stress occurs when cellular concentrations of reactive oxygen species (ROS) exceed the cells’ ability to scavenge them. ROS attack the structures of our cellular components, including the DNA. The resulting DNA lesions are a major source of genomic instability and the mutation load that gives rise to cancer and other human diseases.

The cells primary defense against oxidative DNA lesions is the base excision repair (BER) pathway.

The BER pathway requires the coordinated activity of at least five enzymes including: (1) a DNA glycosylase capable of excising the modified base; (2) an AP-endonuclease, such as APE1, to generate a nick at the lesion site; (3) DNA polymerase β, which performs both lyase and DNA synthesis activities to remove the 5′ dRP (deoxyribonucleotide-phosphate) and fill the resulting gap; and, finally (4) DINA ligase I or DNA ligase III/XRCC1 (X-ray repair cross-complementing protein 1) to seal the nick and complete the repair.