Base excision repair (BER) is a cellular mechanism, studied in the fields of biochemistry and genetics, that repairs damaged DNA throughout the cell cycle. It is responsible primarily for removing small, non-helix-distorting base lesions from the genome. The related nucleotide excision repair pathway repairs bulky helix-distorting lesions. BER is important for removing damaged bases that could otherwise cause mutations by mispairing or lead to breaks in DNA during replication. BER is initiated by DNA glycosylases, which recognize and remove specific damaged or inappropriate bases, forming AP sites. These are then cleaved by an AP endonuclease. The resulting single-strand break can then be processed by either short-patch (where a single nucleotide is replaced) or long-patch BER (where 2–10 new nucleotides are synthesized).

Single bases in DNA can be chemically damaged by a variety of mechanisms, the most common ones being deamination, oxidation, and alkylation. These modifications can affect the ability of the base to hydrogen-bond, resulting in incorrect base-pairing, and, as a consequence, mutations in the DNA. For example, incorporation of adenine across from 8-oxoguanine (right) during DNA replication causes a G:C base pair to be mutated to T:A. Other examples of base lesions repaired by BER include:

In addition to base lesions, the downstream steps of BER are also utilized to repair single-strand breaks.

The choice between short- and long-patch repair is currently under investigation. Various factors are thought to influence this decision, including the type of lesion, the cell cycle stage, and whether the cell is terminally differentiated or actively dividing. Some lesions, such as oxidized or reduced AP sites, are resistant to pol β lyase activity and, therefore, must be processed by long-patch BER.

Pathway preference may differ between organisms, as well. While human cells utilize both short- and long-patch BER, the yeast Saccharomyces cerevisiae was long thought to lack a short-patch pathway because it does not have homologs of several mammalian short-patch proteins, including pol β, DNA ligase III, XRCC1, and the kinase domain of PNKP. The recent discovery that the poly-A polymerase Trf4 possesses 5' dRP lyase activity has challenged this view.

DNA glycosylases are responsible for initial recognition of the lesion. They flip the damaged base out of the double helix, as pictured, and cleave the N-glycosidic bond of the damaged base, leaving an AP site. There are two categories of glycosylases: monofunctional and bifunctional. Monofunctional glycosylases have only glycosylase activity, whereas bifunctional glycosylases also possess AP lyase activity. Therefore, bifunctional glycosylases can convert a base lesion into a single-strand break without the need for an AP endonuclease. β-Elimination of an AP site by a glycosylase-lyase yields a 3' α,β-unsaturated aldehyde adjacent to a 5' phosphate, which differs from the AP endonuclease cleavage product. Some glycosylase-lyases can further perform δ-elimination, which converts the 3' aldehyde to a 3' phosphate. A wide variety of glycosylases have evolved to recognize different damaged bases. Examples of DNA glycosylases include Ogg1, which recognizes 8-oxoguanine, MPG, which recognizes 3-methyladenine, and UNG, which removes uracil from DNA.

The AP endonucleases cleave an AP site to yield a 3' hydroxyl adjacent to a 5' deoxyribosephosphate (dRP). AP endonucleases are divided into two families based on their homology to the ancestral bacterial AP endonucleases endonuclease IV and exonuclease III. Many eukaryotes have members of both families, including the yeast Saccharomyces cerevisiae, in which Apn1 is the EndoIV homolog and Apn2 is related to ExoIII. In humans, two AP endonucleases, APE1 and APE2, have been identified. It is a member of the ExoIII family.

In order for ligation to occur, a DNA strand break must have a hydroxyl on its 3' end and a phosphate on its 5' end. In humans, polynucleotide kinase-phosphatase (PNKP) promotes formation of these ends during BER. This protein has a kinase domain, which phosphorylates 5' hydroxyl ends, and a phosphatase domain, which removes phosphates from 3' ends. Together, these activities ready single-strand breaks with damaged termini for ligation. The AP endonucleases also participate in 3' end processing. Besides opening AP sites, they possess 3' phosphodiesterase activity and can remove a variety of 3' lesions including phosphates, phosphoglycolates, and aldehydes. 3'-Processing must occur before DNA synthesis can initiate because DNA polymerases require a 3' hydroxyl to extend from.