DNA repair !

Cells fix thousands of DNA lesions every day with several repair systems; when one fails, cancer and inherited diseases appear.

Updated 2026-11-01

Key facts

Nucleotide excision repair (NER): removes stretches with UV-induced pyrimidine dimers. Defective in xeroderma pigmentosum.
Mismatch repair (MMR): fixes mispaired bases after replication (MSH2, MLH1, MSH6, PMS2). Defective in Lynch syndrome.
Base excision repair (BER): a glycosylase removes the damaged base (uracil, 8-oxoguanine) and AP endonuclease cuts the empty site.
Double-strand breaks: homologous recombination (BRCA1, BRCA2, accurate; S/G2 phases) or non-homologous end joining (NHEJ, error-prone).
Damage sensing: ATM (double-strand breaks) and ATR (single strand) activate p53 and halt the cell cycle.

Spontaneous damage: cytosine deamination to uracil, loss of purines (AP sites), oxidation by free radicals. External damage: UV, ionising radiation, alkylating agents, tobacco smoke.
Global or transcription-coupled NER: XPC (or a stalled RNA polymerase) detects the distortion, TFIIH (XPB, XPD) opens the helix, XPF and XPG cut on both sides, a polymerase fills in and ligase seals.
MMR: MutSα (MSH2–MSH6) recognises the mismatch and MutLα (MLH1–PMS2) directs the cut on the new strand. Without MMR, microsatellites change length (microsatellite instability, MSI).
Homologous recombination: MRN resects the ends, BRCA2 loads RAD51 onto the single strand and it searches the sister chromatid as a template. Without BRCA, cells rely on PARP and error-prone routes.
NHEJ: Ku70/Ku80 binds the ends, DNA-PKcs brings them together and ligase IV joins them; bases may be lost or gained. It also joins V(D)J segments in lymphocytes.
Fanconi pathway: repairs interstrand crosslinks (cisplatin, mitomycin C, aldehydes); the FANC core complex monoubiquitinates FANCD2–FANCI.
Direct reversal: MGMT removes methyl groups from O⁶-guanine using its own cysteine (a suicide protein).

'Xero-NER, Lynch-MMR, BRCA-HR, Ku-NHEJ'.

PARP inhibitors exploit synthetic lethality in tumours with defective BRCA1/2 (breast, ovary, prostate, pancreas).
MSI-high tumours (MMR deficient) carry many mutations and often respond to immune checkpoint inhibitors.
MGMT promoter methylation in glioblastoma predicts a better response to temozolomide.

Think of the answer, then tap the question to see it.

Which system repairs UV-induced thymine dimers?

Nucleotide excision repair (NER); its failure causes xeroderma pigmentosum.

Which lab finding suggests a mismatch repair defect in a tumour?

Microsatellite instability (MSI) or loss of MLH1, MSH2, MSH6 or PMS2 on immunohistochemistry.

Why are BRCA-deficient tumours sensitive to PARP inhibitors?

Without homologous recombination they depend on PARP for repair; blocking both routes kills the cell (synthetic lethality).

Which double-strand break repair route is more error-prone, and why?

NHEJ: it joins the ends directly, without a homologous template, and can lose or add bases.

Educational information, not medical advice. For any symptom, see a health professional.

Sources: DNA Repair (Reactome, 2026); Mismatch Repair (Reactome, 2026); Nucleotide Excision Repair (Reactome, 2026); Base Excision Repair (Reactome, 2026); HDR through Homologous Recombination (HRR) (Reactome, 2026); Nonhomologous End-Joining (NHEJ) (Reactome, 2026); Textbook of Biochemistry for Medical Students, 6th ed. (Jaypee Brothers Medical Publishers (Vasudevan DM, Sreekumari S, Vaidyanathan K), 2011).

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Representative model, for educational purposes only.