- Depurination is a common type of DNA damage in which a purine base—adenine (A) or guanine (G)—is removed from the DNA molecule, leaving behind an empty site in the sugar-phosphate backbone known as an apurinic site or AP site. This process occurs through the hydrolysis of the N-glycosidic bond that normally connects the purine base to the deoxyribose sugar. As a result, the DNA strand remains intact at the backbone level, but the missing base disrupts the informational content of the sequence. Because purines are more susceptible to this bond cleavage than pyrimidines (cytosine and thymine), depurination is a major source of spontaneous DNA damage in cells.
- Depurination can occur spontaneously under normal physiological conditions, but its frequency increases under stress or in the presence of certain chemical agents. For instance, acidic environments accelerate the hydrolysis of the glycosidic bond, leading to higher rates of base loss. On average, thousands of depurination events occur daily in each human cell, making it one of the most frequent forms of DNA damage. Despite this high frequency, cells have evolved efficient DNA repair mechanisms to manage these lesions and maintain genome stability.
- The biological consequences of depurination can be significant if the damage is not repaired before DNA replication. During replication, DNA polymerases may encounter the AP site and either stall or insert an incorrect nucleotide opposite the missing base. This misincorporation can lead to mutations, such as base substitutions, that contribute to genetic instability. If left unchecked, such mutations may accumulate and play a role in aging, cancer development, and other diseases. In addition, the presence of many AP sites can compromise the structural integrity of DNA, further threatening cellular function.
- Cells primarily address depurination through the base excision repair (BER) pathway. Specialized enzymes known as AP endonucleases recognize AP sites and cleave the DNA backbone near the lesion. This creates an entry point for DNA polymerases to insert the correct nucleotide, followed by ligation to restore the integrity of the strand. The efficiency of this repair pathway is critical in preventing mutagenesis caused by spontaneous depurination. However, when repair mechanisms fail or become overwhelmed, the accumulation of AP sites can contribute to genome instability and disease progression.
