A 32-year-old woman presents to the dermatology clinic with multiple pigmented lesions and severe sunburn after minimal sun exposure. She reports a family history of early-onset skin cancers. On examination, she has freckling in sun-exposed areas and multiple nevi. 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 Presentation and Diagnosis This patient presents with **Xeroderma Pigmentosum (XP)**, a rare autosomal recessive disorder characterized by extreme photosensitivity, pigmentation abnormalities, and a dramatically increased risk of skin cancer (1000-fold higher than general population) [cite:Robbins 10e Ch 7]. ### XPA Gene and Nucleotide Excision Repair **Key Point:** XPA encodes a critical component of the nucleotide excision repair (NER) complex, which is responsible for removing bulky DNA lesions caused by ultraviolet (UV) radiation, particularly thymine dimers. **High-Yield:** The NER pathway has two sub-pathways: - **Global genome repair (GGR):** removes lesions from non-transcribed DNA - **Transcription-coupled repair (TCR):** removes lesions from actively transcribed genes XPA protein is essential for both pathways, acting as a DNA-binding protein that recognizes distorted DNA and recruits other repair factors. ### Mechanism of UV Damage 1. UV-B radiation (280–320 nm) causes thymine dimer formation 2. These lesions distort the DNA double helix 3. NER complex recognizes and excises the damaged segment (typically 24–32 nucleotides) 4. DNA polymerase fills the gap; ligase seals the nick **Clinical Pearl:** Patients with XP must avoid all sun exposure and use high-SPF sunscreen; even indoor fluorescent lighting can trigger reactions in severe cases. ### Why XP Causes Cancer Without functional NER, UV-induced mutations accumulate in skin cells, particularly in genes controlling cell cycle (p53, RB) and apoptosis. This leads to: - Squamous cell carcinoma - Basal cell carcinoma - Melanoma - Often by age 20–30 years **Mnemonic:** **XP = eXcision Problem** — the excision repair pathway is broken. ```mermaid flowchart TD A[UV-B Radiation]:::action --> B[Thymine Dimer Formation]:::outcome B --> C{NER Functional?}:::decision C -->|Yes - Normal| D[Lesion Excised & Repaired]:::action D --> E[Normal DNA]:::outcome C -->|No - XP| F[Lesion Persists]:::urgent F --> G[Mutation Accumulation]:::urgent G --> H[Early-Onset Skin Cancer]:::urgent ```