DNA Damage and Repair Mechanisms
DNA is continually altered by errors of replication and by chemical and physical insults from inside and outside the cell. DNA damage and repair mechanisms are the set of biochemical pathways that detect these lesions and either correct them or trigger cellular responses such as cell-cycle arrest and cell death. Together they maintain the integrity of the genome across cell divisions and over the lifespan of an organism.
Definition
DNA damage and repair mechanisms comprise the cellular pathways that recognise lesions in DNA, restore the correct sequence or structure where possible, and signal damage to the cell-cycle machinery, collectively preserving genome stability.
Scope
This area orients the reader to the principal classes of DNA lesions and to the major repair pathways that counter them: direct reversal and excision repair of base lesions, mismatch repair of replication errors, and the two routes for repairing double-strand breaks. It also covers the surveillance system, the DNA damage response, that couples lesion detection to cell-cycle checkpoints and apoptosis. It is a reference overview of mechanisms; the detailed topics are treated in the child entries.
Sub-topics
Core questions
- What are the major sources and chemical types of DNA damage?
- How do cells choose among distinct repair pathways for different lesions?
- How is damage detection coupled to cell-cycle arrest and to cell death?
- Why does failure of repair contribute to cancer, ageing, and inherited disease?
Key concepts
- Endogenous versus exogenous damage
- Lesion recognition and pathway choice
- Direct reversal and excision repair
- Double-strand break repair
- DNA damage response signalling
- Cell-cycle checkpoints
- Genomic instability
Key theories
- Genome maintenance and the multistage origin of cancer
- Endogenous and environmental agents constantly damage DNA, and a network of repair and damage-response pathways acts as a barrier against the accumulation of mutations; loss of these defences is a route to genomic instability and carcinogenesis.
Mechanisms
DNA lesions arise from spontaneous hydrolysis (depurination and cytosine deamination), oxidation, alkylation, replication errors, and exogenous agents such as ultraviolet light and ionising radiation; Lindahl quantified how chemically unstable DNA is even in the absence of external insult. Distinct repair systems address distinct lesions: base excision repair removes small base modifications, nucleotide excision repair removes bulky helix-distorting adducts, mismatch repair corrects base-base mismatches and insertion/deletion loops left by replication, and double-strand breaks are repaired by homologous recombination or non-homologous end joining. Overlaid on these pathways is the DNA damage response, in which sensor kinases relay a signal to effectors that halt the cell cycle, promote repair, or commit the cell to apoptosis if damage is irreparable.
Clinical relevance
Defects in these pathways underlie a range of human conditions, including cancer-predisposition syndromes, and the same pathways shape how tumours respond to DNA-damaging therapy; the area describes these connections as background to evidence appraisal rather than as guidance for diagnosis or treatment of any individual.
History
The field was built over the second half of the twentieth century, from the discovery of photoreactivation and excision repair to the molecular dissection of the major pathways. Lindahl's recognition of the intrinsic chemical instability of DNA reframed repair as a constant necessity rather than an occasional response, and integrative reviews by Hoeijmakers and by Sancar and colleagues drew the separate pathways together as a coherent genome-maintenance system. The 2015 Nobel Prize in Chemistry to Lindahl, Modrich, and Sancar recognised the mechanistic study of DNA repair.
Key figures
- Tomas Lindahl
- Aziz Sancar
- Paul Modrich
- Stephen Jackson
- Jan Hoeijmakers
Related topics
Seminal works
- lindahl-1993
- hoeijmakers-2001
- sancar-2004
- jackson-bartek-2009
Frequently asked questions
- Why does the cell need so many different repair pathways?
- Different lesions have different chemistry and geometry, so the cell uses specialised systems: small base damage is handled by base excision repair, bulky distortions by nucleotide excision repair, replication mismatches by mismatch repair, and double-strand breaks by recombination or end joining.
- How is DNA repair related to cancer?
- Repair pathways act as a barrier against the accumulation of mutations; when they fail, genomic instability increases and can contribute to cancer, which is why inherited repair defects raise cancer risk.