DNA repair is the collection of processes by which a cell detects and corrects damage to DNA or errors in its sequence arising during copying. These processes preserve genome integrity by reversing chemical modifications, replacing damaged material, or reconnecting broken strands. Repair depends on specialized proteins, including enzymes that recognize lesions and reconstruct DNA. Different pathways address different problems, and repair does not always restore the original sequence perfectly. (ncbi.nlm.nih.gov)
Sources and consequences of DNA damage
DNA is chemically vulnerable even under ordinary cellular conditions. Spontaneous reactions can remove bases or alter their chemical identity; for example, deamination converts cytosine into uracil. Reactive compounds generated during metabolism can damage bases and the sugar–phosphate backbone. Environmental agents, including ultraviolet radiation, ionizing radiation, and certain chemicals, produce additional lesions. These range from small base modifications to bulky adducts, crosslinks, and single- or double-strand breaks. (ncbi.nlm.nih.gov)
Damage is distinct from a mutation. A lesion is a chemical or structural abnormality, whereas a mutation is a lasting change in the DNA sequence. Damage may obstruct DNA replication or transcription, kill a cell, or generate mutations if copied inaccurately. Replication can also introduce mismatched bases or small insertion–deletion loops without prior chemical damage. Repair systems therefore protect both the physical continuity of DNA and the accuracy of its encoded information. (ncbi.nlm.nih.gov)
Direct reversal and excision repair
Direct reversal restores damaged DNA without removing and replacing a segment. Photolyases use light energy to reverse certain ultraviolet-induced pyrimidine dimers in many organisms, although humans lack this repair mechanism. Another example is the removal of an alkyl group from O⁶-methylguanine by the MGMT protein, which accepts the group and becomes inactivated in the process. These mechanisms have relatively narrow substrate specificities. (ncbi.nlm.nih.gov)
Base excision repair (BER) primarily corrects small, non-bulky base abnormalities. A DNA glycosylase recognizes an inappropriate or damaged base and removes it, leaving an abasic site. Subsequent enzymes process the site and its surrounding backbone. A DNA polymerase inserts the appropriate nucleotide or nucleotides, using the intact complementary strand as a template, and DNA ligase seals the remaining nick. BER can replace either a single nucleotide or a short patch. (ncbi.nlm.nih.gov)
Nucleotide excision repair (NER) removes bulky lesions that distort the double helix, including ultraviolet-induced photoproducts. Repair proteins cut the damaged strand on both sides of the lesion and remove the intervening oligonucleotide. DNA synthesis fills the gap, followed by ligation. In humans, global-genome NER surveys DNA broadly, while transcription-coupled NER preferentially addresses lesions that obstruct transcription on the template strand. (ncbi.nlm.nih.gov)
Mismatch repair
DNA mismatch repair corrects mismatched bases and small insertion–deletion loops that escape polymerase proofreading during replication. Its central challenge is identifying the newly synthesized strand, because either member of a mismatched pair could otherwise be replaced. Strand-discrimination mechanisms differ among organisms; methylation-dependent discrimination in some bacteria is not a universal mechanism. (ncbi.nlm.nih.gov)
After mismatch recognition, the system removes a stretch of the new strand containing the error. A polymerase then resynthesizes this region from the parental template, and ligase completes repair. Thus, mismatch repair is distinct from proofreading: proofreading acts during DNA synthesis, whereas mismatch repair provides an additional correction system for errors that remain afterward. (ncbi.nlm.nih.gov)
Repair of strand breaks
Single-strand breaks require restoration of suitable chemical ends, replacement of missing nucleotides where necessary, and ligation. Double-strand breaks are particularly consequential because both strands are interrupted; unrepaired or incorrectly joined breaks can cause loss of genetic material or chromosomal rearrangements. (pubmed.ncbi.nlm.nih.gov)
Homologous recombination repairs breaks by obtaining sequence information from a homologous DNA molecule. In dividing mammalian cells, the sister chromatid is generally the preferred template. Processing exposes single-stranded DNA that pairs with the template, allowing synthesis across the damaged region. This mechanism can accurately recover missing information, although recombination can also produce rearrangements depending on the substrate and pathway used. (pmc.ncbi.nlm.nih.gov)
Non-homologous end joining (NHEJ) reconnects broken DNA ends without requiring an extensive homologous template. Compatible ends may be joined accurately, but end processing can introduce insertions or deletions. NHEJ is important in nonreplicating cells and also participates in programmed V(D)J recombination, which assembles antigen-receptor genes. (niehs.nih.gov)
Coordination and damage tolerance
Repair operates within the broader DNA damage response, which coordinates lesion recognition, signaling, and cell-cycle control. Checkpoints can delay progression, providing time for repair before damaged DNA is copied or separated into daughter cells. These regulatory responses are not themselves equivalent to chemical repair. (ncbi.nlm.nih.gov)
Cells can also tolerate lesions temporarily. Translesion DNA synthesis uses specialized polymerases to copy across damaged templates that block ordinary replication. This bypass does not necessarily remove the lesion and can be mutagenic. Damage tolerance and repair are therefore related but distinct strategies. (pubmed.ncbi.nlm.nih.gov)
Disease relevance and research history
Inherited defects in repair pathways can increase susceptibility to cancer. Lynch syndrome involves inherited abnormalities affecting mismatch repair. BRCA1 and BRCA2 participate in homologous DNA repair, and certain harmful inherited variants increase the risk of breast, ovarian, and other cancers. Increased susceptibility does not mean that cancer is inevitable. Repair defects also influence tumor responses to DNA-damaging treatments and PARP inhibitors. (cancer.gov)
The 2015 Nobel Prize in Chemistry recognized Tomas Lindahl, Paul Modrich, and Aziz Sancar for mechanistic studies of DNA repair. Their work established molecular explanations for base excision repair, mismatch repair, and nucleotide excision repair, respectively. (nobelprize.org)