A 32-year-old Indian woman presents to the dermatology clinic with multiple pigmented lesions on sun-exposed areas of her skin. She reports a family history of early-onset skin cancers and developmental delay in her younger brother. On examination, she has severe photosensitivity and acute erythema after minimal sun exposure. Genetic testing reveals mutations in the XPA gene. Which of the following DNA repair mechanisms is primarily defective in this patient's condition?

Explanation

## Clinical Diagnosis: Xeroderma Pigmentosum (XP) **Key Point:** Xeroderma pigmentosum is an autosomal recessive disorder caused by defects in nucleotide excision repair (NER), most commonly due to mutations in XPA gene. ### Pathophysiology of NER Defect NER is the primary mechanism for removing bulky DNA lesions, particularly **thymine dimers** and **6-4 photoproducts** induced by ultraviolet (UV) radiation. The XPA protein is essential for damage recognition and unwinding of the DNA double helix. **High-Yield:** XPA mutations prevent recognition and removal of UV-induced DNA damage → accumulation of unrepaired lesions → increased mutation rate → early-onset skin cancers (melanoma, squamous cell carcinoma, basal cell carcinoma) by age 10–20 years. ### Clinical Features of XP | Feature | Mechanism | |---------|----------| | Severe photosensitivity | Inability to repair UV-induced lesions | | Pigmented macules on sun-exposed skin | Abnormal melanocyte response to unrepaired DNA damage | | Early-onset skin cancers (1000× increased risk) | Accumulation of mutations from unrepaired lesions | | Neurological symptoms (in 20–30% of cases) | Progressive neurodegeneration; unclear mechanism | | Ocular involvement (keratitis, photophobia) | UV damage to corneal epithelium | ### NER Mechanism (Normal) ```mermaid flowchart LR A[UV-induced DNA lesion<br/>thymine dimer] -->|XPA recognizes damage| B[Helicase unwinds DNA<br/>XPB/XPD] B -->|Endonucleases excise<br/>25-30 nucleotides| C[Damaged oligonucleotide removed] C -->|DNA polymerase fills gap| D[DNA ligase seals nick] D --> E[Lesion repaired] style A fill:#ffcccc style E fill:#ccffcc ``` **Clinical Pearl:** Patients with XP must avoid all sun exposure and use high-SPF sunscreen; even indoor lighting (fluorescent tubes emit some UV) poses risk. **Warning:** Do not confuse XP with other DNA repair disorders: - **Cockayne syndrome** → defective transcription-coupled repair (TCR, a subset of NER) → neurological symptoms without cancer predisposition - **Ataxia-telangiectasia** → ATM gene defect → defective double-strand break repair (homologous recombination) → lymphomas, leukemias ### Why NER and Not Other Pathways? - **BER** repairs small, non-bulky lesions (oxidative damage, alkylation) — not UV-induced lesions - **MMR** corrects base mismatches during replication — not UV damage - **NHEJ** repairs double-strand breaks — UV primarily causes single-strand lesions (thymine dimers) **Mnemonic:** **XP = eXcision Repair Problem** — NER is the excision repair pathway for bulky lesions.