CorpusHuman Anatomy
Cells & TissuesCell process

DNA repair

Also known as: mismatch repair, nucleotide excision repair, base excision repair, homologous recombination, non-homologous end joining, xeroderma pigmentosum, Lynch syndrome

A set of pathways that continually detect and correct DNA damage and replication errors; inherited defects in them cause cancer-predisposition syndromes.

Overview

Each human cell suffers thousands of DNA lesions every day from spontaneous hydrolysis (depurination, deamination of cytosine to uracil), reactive oxygen species, alkylating agents, UV light and ionising radiation. Damage is sensed by the kinases ATM (double-strand breaks) and ATR (single-stranded DNA at stalled forks), which activate checkpoints (via CHK2/CHK1 and p53) to stop the cell cycle while repair proceeds.

Single-strand pathways use the undamaged strand as a template. Base excision repair (BER) handles small base lesions: a DNA glycosylase removes the abnormal base, AP endonuclease cuts the backbone, polymerase β fills the gap and ligase seals it. Nucleotide excision repair (NER) removes bulky, helix-distorting lesions such as UV-induced pyrimidine (thymine) dimers and benzo[a]pyrene adducts by excising a ≈24–32-nucleotide oligonucleotide. Mismatch repair (MMR) corrects replication errors: MSH2–MSH6 recognises the mismatch, MLH1–PMS2 cuts the newly synthesised strand, which is resynthesised.

Double-strand breaks are repaired by homologous recombination (HR) — accurate, using the sister chromatid as template, so restricted to S and G2 (BRCA1, BRCA2, RAD51) — or by non-homologous end joining (NHEJ) — fast but error-prone ligation of broken ends in any phase (Ku, DNA-PKcs, Artemis), also used in V(D)J recombination of lymphocyte receptors. Some lesions are reversed directly, e.g. O⁶-methylguanine by MGMT.

Parts & subdivisions

  1. Base excision repair
    Glycosylase-initiated; deaminated, oxidised (8-oxoguanine) and alkylated bases.
  2. Nucleotide excision repair
    Bulky adducts and UV pyrimidine dimers; XP proteins.
  3. Mismatch repair
    Post-replicative; MSH2, MSH6, MLH1, PMS2.
  4. Homologous recombination
    Error-free double-strand-break repair in S/G2; BRCA1/2.
  5. Non-homologous end joining
    Error-prone double-strand-break repair; V(D)J recombination.

Function

  • Preserves genome integrity.
  • Prevents mutations that lead to cancer and ageing.
  • Enables programmed DNA rearrangements (V(D)J recombination, class switching).

Clinical significance

Xeroderma pigmentosum

Autosomal recessive NER defect: extreme sun sensitivity, freckling and skin cancers (basal cell, squamous cell, melanoma) in childhood.

Lynch syndrome (HNPCC)

Autosomal dominant germline mutation of an MMR gene (MLH1, MSH2, MSH6, PMS2): microsatellite instability, early colorectal (often right-sided), endometrial, ovarian and other cancers. MMR-deficient tumours respond well to immune checkpoint inhibitors.

BRCA1/2 and PARP inhibitors

HR-deficient breast, ovarian, prostate and pancreatic cancers are killed by PARP inhibitors (olaparib) — "synthetic lethality", because blocking single-strand-break repair produces double-strand breaks they cannot fix. Other repair syndromes: ataxia-telangiectasia (ATM), Fanconi anaemia (interstrand cross-link repair), Bloom syndrome (BLM helicase).

Mnemonics

Which repair for which lesion

UV → NER (XP = "Xtremely Photosensitive"); replication mismatch → MMR (Lynch); double-strand break → HR (BRCA) or NHEJ; single base → BER.

Compiled from standard anatomy and physiology references — see the Cells & Tissues sources. For education only; not medical advice.