Curriculum
Module 13 · 65 min
DNA Damage & Repair
Lesions, sensors, repair pathways — and the synthetic-lethality oncology revolution.
CoreClinicalResearch
Topics
What this module covers
- 01Lesion types: SSB, DSB, base damage, crosslinks, mismatches
- 02Repair pathways: BER, NER, MMR, HR, NHEJ, TLS
- 03ATM/ATR signalling and the DNA damage response
- 04BRCA1/2, Fanconi anaemia, Lynch syndrome
- 05Synthetic lethality and PARP inhibitors
- 06DNA damage as a tumour-immunity trigger (cGAS-STING)
Deep dives
Lesson sub-pages
Learning objectives
By the end of this module you will be able to
- L01Match a repair pathway to its substrate and a clinical syndrome of its loss.
- L02Explain the synthetic lethality between BRCA-deficiency and PARP inhibition.
- L03Discuss MMR-deficient tumours' response to immune checkpoint blockade.
Expected takeaways
What you should walk away believing
- →Defective DNA repair predicts both tumour susceptibility and therapeutic vulnerability.
- →MMR-deficient tumours are immune checkpoint-responsive (high neoantigen load).
- →Cells with broken double-strand-break repair often become exquisitely sensitive to single-strand-break accumulation (PARPi).
Core summary
At the Core level
DNA is damaged thousands of times per cell per day. Multiple repair pathways evolved to handle different lesions, and their wiring is non-redundant for some substrates. Inherited or acquired loss of one pathway often exposes a vulnerability — the foundation for modern PARP inhibitor and ATR/CHK1 inhibitor therapy.
Evidence-graded claims
Claims, scored A–F
A
BRCA-deficient cancers are sensitive to PARP inhibitors
Synthetic lethality clinically validated multiple settings.
B
All MMR-deficient cancers respond to PD-1 blockade
Strong response rates; not 100% — exhaustion and HLA loss escape.
D
POLθ inhibitors will succeed where PARP failed
Promising preclinical; clinical data immature.
Quiz
Check your understanding
Q1. Pembrolizumab approval for any MMR-deficient solid tumour was based on:
Q2. Olaparib monotherapy is most effective in:
Flashcards
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Front
DSB repair pathways?
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Suggested reading
Primary literature
- Synthetic lethal targeting of BRCA1/2 by PARP inhibitors — Bryant et al., Nature 2005 ↗
- Mismatch repair deficiency predicts response of solid tumors to PD-1 blockade — Le et al., Science 2017 ↗