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In the cells of an organism, the integrity of DNA is very important because it contains the genetic information of life. However, various internal and external factors can damage DNA, leading to genetic mutations or cell death. Understanding DNA repair mechanisms, especially the role of apurinic/apyrimidinic (AP) endonucleases, is crucial to studying how to protect and repair the genome.
AP endonuclease is an enzyme involved in the DNA base repair pathway. Its main function is to create a nick at the location where DNA deoxyribonucleotides are missing so that the damaged nucleotides can be repaired. In this process, AP endonuclease plays an important role, allowing the organism to restore its genetic code after suffering damage. There are two main AP endonucleases in humans, namely APE1 and APE2. APE1 is considered the most important AP endonuclease, responsible for more than 95% of intracellular activities.
APE1 is a Class II AP endonuclease, which is crucial for the basic repair process and usually requires Mg2+ in the active site.
The structure of APE1 is very delicate, and its amino acid residues can react selectively with the AP site. The active site of APE1 is particularly important for maintaining DNA stability because it ensures that the missing portion of DNA reaches the cutting site to initiate the repair process. Through further hydrogen bonding, APE1 can stabilize the surrounding phosphate groups, thereby completing the cleavage of the DNA backbone.
Mechanism of AP endonuclease
APE1 forms the nick via a simple acyl substitution mechanism. First, the Asp210 residue in the active site deprotonates water molecules, and then performs a nucleophilic attack to cleave the phosphate group on the 5' side of the AP site. This process generates a free 5’ phosphate group and a 3’-hydroxyl group upstream of the normal nucleotide, which are stabilized by Mg2+.
Research shows that the activity of APE1 reaches its maximum at pH 7.5, which is related to the hydrogen bond stability of the active site.
Inhibition of APE1
Not only is APE1 critical for cellular DNA repair, it has also become a target for inhibitors. Known APE1 inhibitors include nitroindole-2-carboxylic acid (NCA) and lucadon. Compounds with these structures are similar to the abasic deoxyribose sugar ring and can interact with the active site of APE1, thereby preventing it from catalyzing other reactions.
The relationship between APE1 and cancer treatment
Due to its gene repair function in organisms, APE1 has become an important research target in cancer research. Researchers are trying to increase the sensitivity of tumor cells during chemotherapy by inhibiting APE1, making it difficult for them to survive after treatment. This provides new ideas for cancer treatment to some extent.
The role of APE2
Compared with APE1, APE2 has weaker AP endonuclease activity, but its 3’-5’ exonuclease activity is relatively strong and can hydrolyze DNA under a variety of conditions. This allows APE2 to play a key role in the response of cells to DNA damage after being subjected to oxidative stress, further promoting the stability and repair ability of DNA.
Whether it is APE1 or APE2, their role in the DNA repair process shows the complexity and mystery of life. In future scientific research, how to deeply understand the mechanism of these enzymes may reveal more mysteries about the nature of life. What unknown force drives these enzymes to precisely repair our genetic code?
