A 32-year-old Indian woman presents to the dermatology clinic with multiple pigmented lesions and severe sunburn after minimal sun exposure. On examination, she has freckling on sun-exposed areas, photophobia, and progressive vision loss. Genetic testing reveals mutations in the XPA gene. Which of the following DNA repair mechanisms is primarily defective in this patient's condition?

## 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 Nucleotide excision repair is the primary mechanism for removing UV-induced DNA lesions, particularly thymine dimers and 6-4 photoproducts. The NER pathway involves: 1. Recognition of DNA damage (XPA protein is critical for damage recognition and verification) 2. Unwinding of DNA helix (XPB and XPD helicases) 3. Excision of damaged oligonucleotide (25–30 nucleotides) 4. DNA synthesis by DNA polymerase δ 5. Ligation by DNA ligase **High-Yield:** XPA mutations specifically impair the damage recognition and verification step, preventing the entire NER cascade from initiating. ### Clinical Features of XP | Feature | Mechanism | |---------|----------| | Severe photosensitivity | Inability to repair UV-induced thymine dimers | | Pigmentation abnormalities (freckling, hypopigmentation) | Melanocyte dysfunction due to accumulated DNA damage | | Ocular involvement (photophobia, keratitis, corneal opacification) | UV damage accumulation in corneal epithelium | | Neurological degeneration (progressive) | Spontaneous DNA damage accumulation in neurons | | 1000-fold increased skin cancer risk | Unrepaired mutations leading to oncogenic transformation | **Clinical Pearl:** Patients with XP must avoid all sun exposure and use strict photoprotection. Even indoor fluorescent lighting can cause damage in some cases. ### Why NER and Not Other Repair Pathways? - **BER** handles oxidative damage and small lesions (not UV-induced dimers) - **MMR** corrects base mismatches post-replication (not UV lesions) - **NHEJ** repairs double-strand breaks (not relevant to UV photoproducts) **Mnemonic:** **NER = UV** — Nucleotide Excision Repair handles UV damage. [cite:Robbins 10e Ch 7]