## Xeroderma Pigmentosum and Nucleotide Excision Repair **Key Point:** Xeroderma pigmentosum (XP) is caused by defects in nucleotide excision repair (NER), most commonly in XPA protein, which recognizes and binds to DNA lesions (especially thymine dimers from UV radiation). ### NER Pathway and XP Complementation Groups | XP Group | Defective Protein | Function | Consequence | |---|---|---|---| | XPA | XPA (most common) | Lesion recognition & binding | Inability to detect UV-induced damage | | XPB | TFIIH helicase | Unwinding DNA around lesion | Impaired helix unwinding | | XPC | XPC protein | Alternative lesion recognition | Reduced NER initiation | | XPD | TFIIH helicase | 3'→5' helicase activity | Defective strand unwinding | | XPE | DDB2 protein | Damage-binding protein | Reduced lesion detection | | XPF | XPF endonuclease | 5' incision | No 5' strand cleavage | | XPG | XPG endonuclease | 3' incision | No 3' strand cleavage | **High-Yield:** XPA is the most frequently affected gene in XP (~25–30% of cases). It is the first step in NER — recognition of the lesion. Without XPA, the entire NER pathway cannot be initiated. **Mnemonic:** **XPA = eXcision Pathway Anchor** — XPA anchors the recognition step of NER. ### Clinical Features of XP - Extreme photosensitivity (severe sunburn after minimal sun exposure) - Pigmentary changes (hyperpigmentation and hypopigmentation) - High incidence of skin cancers (melanoma, squamous cell carcinoma) by age 10–20 years - Neurological degeneration in ~30% of cases - Normal lifespan if sun exposure is avoided **Clinical Pearl:** Patients with XP must avoid all UV exposure (sunscreen SPF 50+, protective clothing, avoid midday sun). Early diagnosis and strict photoprotection can significantly reduce cancer risk.
Sign up free to access AI-powered MCQ practice with detailed explanations and adaptive learning.