Cellular mechanisms that fix DNA damage, often targeted in cancer therapy.DNA repair is the set of molecular processes by which a cell detects and corrects damage to its genetic material. DNA is chemically fragile: ultraviolet light fuses adjacent bases together, radiation snaps the sugar-phosphate backbone, and ordinary metabolic by-products alter bases or create breaks. Left unrepaired, such lesions block the machinery that copies and reads DNA, or they get converted into permanent mutations when the cell divides. Cells therefore maintain a standing crew of enzymes that patrol the genome, recognise specific kinds of damage, and restore the original sequence.
The importance of repair is easiest to see when it fails. Inherited defects in repair pathways cause diseases with dramatically elevated cancer risk and premature ageing, and many tumours disable a repair route in order to survive the mutations that drive them. That dependence is also an opportunity: if a cancer cell has already lost one repair pathway, blocking a second one can kill it selectively while normal cells cope. This idea, called synthetic lethality, is the basis of several targeted cancer drugs.
DNA repair explains why most DNA damage does not become a mutation, why some people inherit strong cancer predispositions, and why certain tumours respond to treatments that damage DNA, such as radiation and platinum-based chemotherapy. It also underlies the accuracy of genome copying across billions of cell divisions in a human lifetime.
The existence of repair was inferred in the 1940s from the observation that bacteria can recover from ultraviolet doses that would otherwise be lethal. The first concrete pathway, nucleotide excision repair, was worked out in the 1960s, and the link between repair defects and human disease was established in 1968 when James Cleaver showed that cells from patients with the inherited disorder xeroderma pigmentosum cannot remove UV damage. The 2015 Nobel Prize in Chemistry recognised mechanistic studies of DNA repair by Tomas Lindahl, Paul Modrich and Aziz Sancar.
Different lesions are handled by dedicated pathways. Base excision repair removes a single altered base and patches the gap. Nucleotide excision repair cuts out a short stretch of DNA around a bulky distortion, such as a UV-induced crosslink, and fills it in using the intact opposite strand as a template. Mismatch repair corrects copying errors left behind by the replication machinery. Double-strand breaks, the most dangerous lesion, are repaired either by non-homologous end joining, which simply glues the ends back together and can lose a few bases, or by homologous recombination, which uses a sister copy of the chromosome as a template and is therefore accurate.
A common logic runs through these systems: an enzyme recognises the damage, a nuclease or glycosylase removes the offending piece, a polymerase synthesises replacement DNA, and a ligase seals the final nick. Because the opposite strand is usually intact, the cell almost always has the information needed to restore the correct sequence rather than merely patch the break.
Repair status guides cancer treatment: PARP inhibitors exploit defective homologous recombination in tumours, and platinum drugs and radiotherapy work partly because cancer cells repair DNA less faithfully than healthy tissue. Repair enzymes are also workhorses of laboratory molecular biology, used in cloning, sequencing and gene editing.
A single human cell is estimated to suffer tens of thousands of DNA-damaging events per day, nearly all of which are repaired before the cell next divides.