Each pathway repairs a different kind of damage
Expansion
| Pathway | Repairs | Disease of failure |
|---|---|---|
| Nucleotide excision repair | UV pyrimidine dimers | Xeroderma pigmentosum |
| Mismatch repair | Replication errors | Lynch syndrome (HNPCC) |
| Base excision repair | Single damaged bases | MYH-associated polyposis |
| Homologous recombination | Double strand breaks | BRCA1/2, Fanconi anaemia |
| Non-homologous end joining | Double strand breaks | Ataxia telangiectasia |
“Every repair pathway has a cancer syndrome attached to it.”
Xeroderma pigmentosum: severe photosensitivity, freckling and multiple skin cancers in childhood, requiring complete sun avoidance.
Lynch syndrome: mismatch repair failure produces microsatellite instability, with right sided colorectal cancer, endometrial cancer and others, occurring young and with few polyps. It is why all colorectal and endometrial cancers are now tested for mismatch repair deficiency, and why those tumours respond to immunotherapy.
BRCA and PARP inhibitors are the clearest therapeutic application. BRCA deficient cells have lost homologous recombination, so blocking the alternative PARP pathway leaves them with no repair at all. Normal cells retain both, so they survive. This is synthetic lethality.
Ataxia telangiectasia additionally causes marked radiosensitivity, which is a practical hazard in imaging and radiotherapy.