An apurinic/apyrimidinic (AP) site, or abasic site, is a location in DNA where the base—the “rung” of the DNA ladder—is missing, leaving a gap in the genetic sequence. While the sugar-phosphate backbone of the DNA strand remains intact, the genetic information at that position is lost. This is one of the most frequent types of DNA damage in a living cell. The constant formation of these sites highlights the ongoing threat to a cell’s genetic material from both internal and external sources.
Formation of Abasic Sites
Abasic sites form in two primary ways: spontaneously or by cellular enzymes. Spontaneous formation occurs through hydrolysis, where the N-glycosidic bond linking a purine base (adenine or guanine) to the DNA’s sugar backbone breaks. This cleavage happens thousands of times daily in a single human cell due to DNA’s presence in a water-based medium.
The second pathway is enzymatic, carried out by enzymes called DNA glycosylases that scan the genome for damaged or incorrect bases. When a glycosylase finds a damaged base, it severs the N-glycosidic bond to remove it. This action intentionally creates a temporary abasic site, which is the first step in a larger repair mechanism. This process allows the cell to fix a different, more harmful type of DNA damage.
Cellular Impact of Abasic Sites
An unrepaired abasic site disrupts DNA replication and transcription. When a DNA polymerase, the enzyme that copies DNA, encounters an abasic site, it lacks the template to insert the correct nucleotide. The replication machinery often inserts an adenine base opposite the gap. This “A-rule” is a source of point mutations that alter the genetic code.
These lesions are also a physical impediment to cellular machinery. An abasic site can cause DNA polymerase to stall, halting replication. RNA polymerase can also be blocked, stopping the production of proteins and other functional molecules. This blockage can cause replication forks to collapse and lead to more severe DNA damage, such as single-strand breaks.
The Base Excision Repair Pathway
Cells use the Base Excision Repair (BER) pathway to counteract the constant formation of abasic sites. The repair begins when an AP endonuclease, or APE1 in humans, recognizes the abasic site. The enzyme then cuts the DNA’s phosphodiester backbone next to the site, creating a nick.
After the nick is made, other enzymes continue the repair. A DNA polymerase arrives and removes the baseless sugar-phosphate remnant. The polymerase then uses the opposite strand as a template to insert the correct base, filling the gap and restoring the genetic sequence.
The final step is sealing the nick in the DNA backbone, a task performed by the enzyme DNA ligase. It creates a new phosphodiester bond, closing the gap and restoring the strand’s integrity. This completes the repair, leaving the DNA molecule ready for normal cellular functions like replication and transcription.
Abasic Sites and Human Health
The Base Excision Repair pathway’s efficiency can diminish, and defects can arise in the genes that code for its enzymes. If abasic sites form faster than they can be repaired, the lesions accumulate. This buildup can lead to more mutations during DNA replication, a contributing factor in the development of various cancers.
Genome integrity is also linked to neurological health and the aging process. An accumulation of DNA damage, including abasic sites, is observed in some neurodegenerative diseases. Declining DNA repair efficiency is also a component of biological aging, as the cumulative effect of unrepaired lesions can compromise cell function.