AP Sites (Apurinic/Apyrimidinic Sites(

AP (apurinic/apyrimidinic) sites are deoxyribose residues in the DNA that have lost the purine or pyrimidine bases.

 1. Occurrence

 AP sites are generated by a variety of mechanisms:

1.1. Spontaneous Base Loss 

The glycosylic bond joining the base to the deoxyribose in the DNA backbone is relatively unstable and is cleaved, even under physiological conditions, at a rate incompatible with life. It is estimated that at normal pH and temperature there are base losses at rates of about 10^–12 s^–1 for double-stranded DNA and 10^–10 s^–1 for single-stranded DNA. This means that humans (with about 1.2 × 10¹⁰ bp per diploid cell) lose about 1 base per minute per cell, or, taking into account that there are about 1013 cells in the human body, lose 1.5 × 10¹⁶ bases from their DNA daily. The rate of base loss is greatly accelerated by heat and low pH. Because of higher susceptibility of their N9 atom to nucleophilic attack, the purine bases are hydrolyzed at a rate about 100-fold faster than are pyrimidines (1). In fact, because of this unique property of purines, one of the procedures for chemical DNA sequencing reactions consists of heating the DNA at acidic pH, followed by cleavage of the resulting AP site by alkali treatment.

1.2. Ionizing Radiation 

Ionizing radiation most often causes base reduction, oxidation, or fragmentation. In particular, a urea residue attached to the deoxyribose is a relatively common product of ionizing radiation and, for all practical purposes, may be considered an AP site. Such radiation causes base loss by either (a) generating reactive oxygen species that attack and destroy bases or (b) direct hits by ionizing  radiation.

1.3. Glycosylases 

There are about a dozen DNA glycosylases with varying degrees of specificity for bases with minor modifications: uracil glycosylase, 3-methyladenine DNA glycosylase, 8-oxoguanine DNA glycosylase, and glycosylases that act on mismatches, such as T-G glycosylase, specific for the T residue, and A-G glycosylase, specific for the A residue. These enzymes release the modified, abnormal, or mismatched bases by hydrolyzing the glycosylic bond linking the base to the deoxyribose. Most of the glycosylases have dual enzymatic activities in that, after cleaving the glycosylic bond, they also cleave the phosphodiester bond by b-elimination. However, some, such as uracil glycosylase, are “pure” glycosylases with no such associated AP lyase activity.

2. Consequences

 AP sites in DNA are, in fact, very unstable. Even at physiological pH and temperature, the abasic sugar can be eliminated by b–d elimination. The presence of the divalent metal ions that would be expected in biological fluids greatly accelerates the cleavage reaction. The reaction may be further accelerated by basic proteins, such as cytochrome c. Consequently, AP sites as such do not constitute an important lesion interfering with cell survival. In contrast to b-elimination, however, which occurs readily under a variety of conditions, the d-elimination reaction, which in combination with b-elimination would release the abasic deoxyribose from DNA, does not occur at physiologically relevant rates. AP endonucleases hydrolyze the phosphodiester bond 5 to the AP site, and Escherichia coli cells that lack this enzyme are sensitive to agents that generate AP sites or fragmented deoxyribose residues.

References

1. T. Lindahl (1976) Nature 259, 64–66. 

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