Base Excision Repair

Base excision repair (BER) is a DNA repair pathway that corrects chemically altered or inappropriate bases in DNA, particularly lesions that do not greatly distort the double helix. Repair usually begins when a DNA glycosylase removes an individual base, leaving a baseless sugar in the DNA backbone. Subsequent reactions process this site, replace the affected DNA, and seal the strand. BER helps preserve genetic information against spontaneous chemical deterioration and damage caused by environmental agents. (nobelprize.org)

Damage recognized by BER

DNA bases can undergo chemical changes without the DNA strand immediately breaking. BER recognizes many such alterations, including products of oxidation, deamination, and certain forms of alkylation. Its characteristic starting point is recognition of the altered base rather than removal of a large, structurally distorted DNA segment. (nobelprize.org)

Two examples illustrate the pathway’s specificity:

• Uracil in DNA: deamination converts cytosine into uracil. Uracil-DNA glycosylase removes the uracil, allowing downstream repair to restore cytosine using the opposing guanine as a template. The glycosylase reaction itself releases the base without initially cutting the sugar–phosphate backbone. (pubmed.ncbi.nlm.nih.gov)
• 8-Oxoguanine: oxidation of guanine produces 8-oxoguanine, which can mispair with adenine during DNA replication and thereby promote mutation. The human glycosylase OGG1 preferentially removes this lesion when it is paired with cytosine. (pubmed.ncbi.nlm.nih.gov)

BER therefore comprises several lesion-recognition routes that converge on related downstream processing reactions, rather than one enzyme system with identical specificity for every damaged base. (nobelprize.org)

Molecular mechanism

Base recognition and excision

A DNA glycosylase is an enzyme that recognizes particular base substrates and cleaves the N-glycosidic bond connecting a base to its deoxyribose sugar. Many glycosylases inspect the substrate by positioning the target base outside the DNA helix in a catalytic pocket. Excision leaves an abasic site, also called an AP site, meaning apurinic or apyrimidinic site. The sugar and surrounding backbone remain after the initial base-removal reaction. (pubmed.ncbi.nlm.nih.gov)

Glycosylases differ in their catalytic capabilities. Some remove only the base; others also possess AP-lyase activity that cleaves the backbone at the resulting abasic site. Mammalian OGG1, for example, can catalyze both base removal and processing of the baseless sugar. The resulting intermediate determines which downstream reactions are needed. (pubmed.ncbi.nlm.nih.gov)

Backbone incision and end processing

In the canonical mammalian pathway initiated by a base-removing glycosylase, AP endonuclease APE1 cuts a phosphodiester bond immediately on the $5'$ side of the abasic site. This creates a $3'$-hydroxyl group and a $5'$-deoxyribose phosphate residue. The hydroxyl provides an end from which repair synthesis can proceed, whereas the residual sugar–phosphate group must be removed before the strand can be fully sealed. (pubmed.ncbi.nlm.nih.gov)

DNA polymerase β has two relevant activities: it synthesizes replacement DNA and removes the $5'$-deoxyribose phosphate through its dRP-lyase activity. These are distinct catalytic functions within the same protein. Thus, successful BER requires not merely insertion of the correct base but also production of chemically suitable DNA ends. (pubmed.ncbi.nlm.nih.gov)

Repair synthesis and ligation

A polymerase fills the repair gap using the complementary strand as a template. A DNA ligase then seals the remaining nick, restoring continuity of the backbone. A uracil–guanine substrate has been repaired experimentally using purified human uracil-DNA glycosylase, AP endonuclease, polymerase β, and ligase III. The accessory protein XRCC1 interacts with polymerase β and ligase III and functions as a coordinating scaffold rather than as the enzyme that directly performs these reactions. (pmc.ncbi.nlm.nih.gov)

Short-patch and long-patch repair

BER can replace either a single nucleotide or a short stretch of DNA. These alternatives are termed short-patch and long-patch repair.

These distinctions have been established through biochemical reconstitution with purified proteins. (pmc.ncbi.nlm.nih.gov)

In long-patch repair, synthesis displaces part of the existing strand, generating a flap containing the material to be removed. Flap endonuclease 1, or FEN1, cuts this structure. A PCNA-dependent human repair system has been reconstructed with AP endonuclease, replication factor C, PCNA, FEN1, polymerase δ, and ligase I. “Long-patch” describes the extent of replacement synthesis; it does not mean that the initiating lesion must itself be large. (pubmed.ncbi.nlm.nih.gov)

Nuclear and mitochondrial repair

BER operates in both nuclear and mitochondrial DNA, but the participating polymerases and their relative contributions need not be identical. Human polymerase γ can perform single-nucleotide gap filling and remove deoxyribose phosphate in a purified mitochondrial BER system. (pubmed.ncbi.nlm.nih.gov)

The older description of polymerase γ as the only mitochondrial DNA polymerase is incomplete. Experimental studies have detected polymerase β in mitochondria from several mammalian cell types and have demonstrated its participation in mitochondrial repair. Its contribution should therefore be described in relation to the tissue or experimental system studied, rather than assumed to be absent from mitochondria. (pubmed.ncbi.nlm.nih.gov)

Roles beyond damage removal

BER machinery also participates in regulated changes to DNA methylation. In one route of active demethylation, TET enzymes oxidize methylated cytosine derivatives, and thymine DNA glycosylase removes products including 5-formylcytosine and 5-carboxylcytosine. Downstream repair can replace the excised residue with unmodified cytosine. This connects base excision to epigenetic regulation: its substrates are not always accidental damage, but can also be intermediates in controlled modification of DNA. (pubmed.ncbi.nlm.nih.gov)

Biological significance and limitations

An established human disease connection is MUTYH-associated polyposis. MUTYH encodes a DNA glycosylase involved in base excision repair; pathogenic variants affecting both inherited copies cause an autosomal recessive disorder associated with substantially increased colorectal cancer risk. This illustrates how loss of a particular lesion-processing activity can compromise genome maintenance. (medlineplus.gov)

Repair is not automatically harmless at every intermediate stage. BER temporarily produces abasic sites and strand interruptions. When several lesions occur close together, particularly on opposing strands, their processing can generate a double-strand break or increase mutability. Experiments with clustered lesions show that the order and spacing of lesion processing influence whether repair restores the DNA or produces more consequential damage. (pmc.ncbi.nlm.nih.gov)

BER is also distinct from two other major excision pathways. Nucleotide excision repair removes a DNA segment containing lesions such as ultraviolet-induced damage, whereas DNA mismatch repair corrects replication-associated pairing errors. The defining feature of BER is its initiation through removal of an individual base. (nobelprize.org)

Discovery

A foundational discovery was Tomas Lindahl’s identification in 1974 of an enzyme from bacterial Escherichia coli that released uracil from DNA containing deaminated cytosine. The finding demonstrated a repair reaction directed at the base–sugar bond rather than initial cleavage of the DNA backbone. (pubmed.ncbi.nlm.nih.gov)

Subsequent biochemical studies identified the downstream activities and reconstructed repair with purified human proteins. Lindahl shared the 2015 Nobel Prize in Chemistry with Paul Modrich and Aziz Sancar for mechanistic studies of DNA repair, recognizing work on base excision repair, mismatch repair, and nucleotide excision repair, respectively. (pmc.ncbi.nlm.nih.gov)

References

1. Scientific Background on the Nobel Prize in Chemistry 2015: Mechanistic Studies of DNA Repairnobelprize.org
2. An N-glycosidase from Escherichia coli that releases free uracil from DNA containing deaminated cytosine residuespubmed.ncbi.nlm.nih.gov
3. A mammalian DNA repair enzyme that excises oxidatively damaged guanines maps to a locus frequently lost in lung cancerpubmed.ncbi.nlm.nih.gov
4. Reconstitution of DNA base excision-repair with purified human proteins: interaction between DNA polymerase beta and the XRCC1 proteinpmc.ncbi.nlm.nih.gov
5. Modulation of the 5'-deoxyribose-5-phosphate lyase and DNA synthesis activities of mammalian DNA polymerase beta by apurinic/apyrimidinic endonuclease 1pubmed.ncbi.nlm.nih.gov
6. Excision of deoxyribose phosphate residues by DNA polymerase beta during DNA repairpubmed.ncbi.nlm.nih.gov
7. Human DNA polymerase beta deoxyribose phosphate lyase. Substrate specificity and catalytic mechanismpubmed.ncbi.nlm.nih.gov
8. Reconstitution of proliferating cell nuclear antigen-dependent repair of apurinic/apyrimidinic sites with purified human proteinspubmed.ncbi.nlm.nih.gov
9. Identification of 5'-deoxyribose phosphate lyase activity in human DNA polymerase gamma and its role in mitochondrial base excision repair in vitropubmed.ncbi.nlm.nih.gov
10. DNA polymerase β outperforms DNA polymerase γ in key mitochondrial base excision repair activitiespubmed.ncbi.nlm.nih.gov
11. DNA Polymerase Beta Participates in Mitochondrial DNA Repairpubmed.ncbi.nlm.nih.gov
12. Tet-mediated formation of 5-carboxylcytosine and its excision by TDG in mammalian DNApubmed.ncbi.nlm.nih.gov