## Nucleotide Excision Repair (NER): Substrate Specificity ### NER Pathway Overview Nucleotide Excision Repair (NER) is a versatile DNA repair mechanism that removes bulky, distorting lesions from DNA. It is the primary pathway for repairing UV-induced damage and chemical adducts. ### Substrates Recognized by NER **Key Point:** NER specifically recognizes and repairs **thymine dimers** (from UV radiation) and **bulky DNA adducts** (from chemicals like benzo[a]pyrene, aflatoxins). These lesions distort the DNA helix structure, triggering recognition by XPA and other NER proteins. ### Mechanism 1. **Recognition:** XPA protein (along with XPC and other factors) scans DNA for helix-distorting lesions 2. **Unwinding:** TFIIH helicase unwinds DNA around the lesion 3. **Excision:** Endonucleases (XPF-ERCC1) cut the damaged strand on both sides of the lesion 4. **Resynthesis:** DNA polymerase fills the gap; ligase seals the nick ### High-Yield: **High-Yield:** XPA mutations cause **Xeroderma Pigmentosum (XP)**, characterized by extreme UV sensitivity, severe sunburn, and 1000-fold increased risk of skin cancer. XP patients cannot repair thymine dimers. ### Comparison of DNA Repair Pathways | Repair Pathway | Substrate | Enzyme Defect Example | Disease | |---|---|---|---| | **NER** | Thymine dimers, bulky adducts | XPA, XPC | Xeroderma Pigmentosum | | Base Excision Repair (BER) | Depurination, deamination, oxidative damage | APEX1, OGG1 | Lynch syndrome (mismatch repair) | | Mismatch Repair (MMR) | Mismatched bases | MLH1, MSH2 | Lynch syndrome, HNPCC | | Homologous Recombination (HR) | Double-strand breaks | BRCA1, BRCA2 | Breast/ovarian cancer | ### Clinical Pearl: **Clinical Pearl:** Patients with XP must avoid all UV exposure (including sunlight) and use protective clothing and sunscreen. Even brief sun exposure can cause severe burns and accelerate skin cancer development.
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