You’re going to see DNA repair questions over and over in Q-banks because they’re perfect “one-vignette, five-mechanism” traps: the stem gives you one lesion, and the answer choices list every repair pathway you’ve ever heard of. The key to scoring points isn’t just knowing the right mechanism—it’s knowing why each distractor is wrong.
Tag: Biochemistry > DNA/RNA/Nucleic Acids
The Clinical Vignette (Q-bank style)
A 7-year-old child has progressive neurologic dysfunction, photosensitivity, and multiple skin cancers. The parents report the child develops severe sunburns after minimal sun exposure. Physical exam shows numerous freckle-like hyperpigmented lesions on sun-exposed areas. A skin biopsy shows markedly increased mutations after UV exposure. Which of the following DNA repair mechanisms is most likely defective?
A. Base excision repair
B. Mismatch repair
C. Nucleotide excision repair
D. Nonhomologous end joining
E. Homologous recombination
Step-by-Step: What the Stem Is Really Saying
The giveaway triad is:
- Photosensitivity
- Skin cancers
- UV-induced DNA damage
UV light causes pyrimidine (thymine) dimers—bulky helix-distorting lesions. The main pathway to fix bulky adducts and thymine dimers is:
✅ Correct Answer: C. Nucleotide excision repair (NER)
The Correct Answer: Nucleotide Excision Repair (NER)
What it fixes (test this)
NER repairs bulky, helix-distorting lesions, especially:
- UV-induced pyrimidine dimers (thymine dimers)
- Chemical adducts (e.g., from smoke/carcinogens)
How it works (high-yield sequence)
- Recognition of distortion
- Excision of a short single-stranded DNA segment containing the lesion (endonuclease cut on both sides)
- DNA polymerase fills
- DNA ligase seals
Classic disease associations
| Disorder | Defect | Key clinical clues |
|---|---|---|
| Xeroderma pigmentosum (XP) | NER | Severe photosensitivity, early skin cancers |
| Cockayne syndrome | Transcription-coupled NER | Photosensitivity + neurodevelopmental issues, no increased cancer risk classically |
USMLE hook: XP = can’t repair UV damage → pyrimidine dimers persist → mutations → skin cancers.
Now Kill the Distractors (Why Each Answer Choice Matters)
A. Base excision repair (BER) — Wrong here
What BER actually fixes: small, non–helix-distorting base lesions, like:
- Spontaneous deamination (C → U)
- Depurination (loss of A/G base)
- Oxidative damage (e.g., 8-oxoG)
Core enzymes:
- DNA glycosylase removes the damaged base → AP (abasic) site
- AP endonuclease cuts backbone
- Polymerase + ligase patch it
Why it’s wrong in this vignette: UV thymine dimers are bulky and helix-distorting, which is NER territory, not BER.
Quick contrast:
- BER = “single bad letter”
- NER = “wrinkled page”
B. Mismatch repair (MMR) — Wrong here
What MMR fixes: replication errors that escape proofreading:
- Base-base mismatches
- Small insertion/deletion loops (microsatellites)
High-yield association: Lynch syndrome
- Genes: MSH2, MLH1, MSH6, PMS2
- Leads to microsatellite instability
- Colon and endometrial cancers are big board favorites
Why it’s wrong in this vignette: the stem screams UV damage/photosensitivity, not inherited colon cancer risk or replication slippage.
USMLE clue: “Microsatellite instability” = MMR.
D. Nonhomologous end joining (NHEJ) — Wrong here
What it fixes: double-strand breaks (DSBs) by directly ligating ends.
- Fast, works in G1
- Error-prone (can lose nucleotides → small deletions)
Key proteins to recognize:
- Ku proteins bind DNA ends
- DNA-PK, ligase IV (often mentioned in more advanced resources)
Disease associations (high-yield):
- Defects can cause SCID-like phenotypes due to impaired V(D)J recombination (DSB repair is required for antibody/TCR diversity)
Why it’s wrong in this vignette: UV causes pyrimidine dimers, not DSBs. NHEJ is about “broken chromosome,” not “sun damage.”
E. Homologous recombination (HR) — Wrong here
What it fixes: double-strand breaks using a sister chromatid as a template
- Accurate, “high-fidelity”
- Occurs in S/G2
High-yield gene association:
- BRCA1/BRCA2 are involved in HR
- Defects → increased risk of breast/ovarian cancer
Why it’s wrong in this vignette: again, the lesion is not a DSB. Plus, the clinical picture points to UV sensitivity and early skin cancers (XP), not BRCA-type cancers.
Rapid-Fire “Lesion → Repair” Map (Memorize This Table)
| Damage / scenario | Repair pathway | High-yield buzzwords |
|---|---|---|
| UV thymine dimers, bulky adducts | NER | Xeroderma pigmentosum, “bulky helix distortion” |
| Deamination, depurination, oxidation | BER | DNA glycosylase, AP endonuclease |
| Replication mismatch, microsatellites | MMR | Lynch syndrome, MSI |
| Double-strand breaks (G1) | NHEJ | Ku proteins, error-prone, V(D)J |
| Double-strand breaks (S/G2) | HR | BRCA1/2, high fidelity |
Common Step Traps (and How to Avoid Them)
Trap 1: Confusing NER with BER
- Bulky + helix distortion = NER
- Single-base chemical change = BER
Trap 2: Over-calling “repair” as mismatch repair
MMR is specifically post-replication cleanup (think: polymerase slipped). If the stem mentions:
- microsatellites
- Lynch
- right-sided colon cancer …then MMR is your lane.
Trap 3: Treating all cancers like BRCA
BRCA = HR defect = double-strand break repair problem.
XP = NER defect = UV damage problem.
10-Second Exam-Day Summary
- UV light → thymine dimers → NER
- Small base damage → BER
- Replication mismatch → MMR
- DSB (G1) → NHEJ (error-prone)
- DSB (S/G2) → HR (BRCA, accurate)