Which of the following is the most common type of DNA damage caused by ultraviolet (UV) radiation that requires nucleotide excision repair (NER)?

Explanation

## UV-Induced DNA Damage and Repair ### Most Common UV Lesion: Thymine Dimers **Key Point:** Thymine dimers (cyclobutane pyrimidine dimers, CPDs) are the predominant DNA lesions induced by UV-B and UV-C radiation, accounting for ~75% of all UV-induced photoproducts. ### Mechanism of Formation UV radiation (particularly 260–280 nm wavelength) causes adjacent thymine bases on the same DNA strand to form covalent cyclobutane rings: - Occurs most frequently at TT and TC dinucleotides - Creates a bulky lesion that distorts the DNA helix - Blocks DNA polymerase and transcription machinery ### Nucleotide Excision Repair (NER) Pathway Thymine dimers are recognized and removed by NER, which involves: | Step | Enzyme/Complex | Function | |------|---|---| | Recognition | XPC-HR23B | Detects distortion in DNA helix | | Unwinding | TFIIH (XPB, XPD) | Unwinds DNA around lesion | | Incision | XPF-ERCC1, XPG | Cuts 5' and 3' sides of lesion | | Synthesis | DNA Pol δ/ε | Fills in 25–30 nucleotide gap | | Ligation | DNA ligase | Seals nick | **High-Yield:** Defects in NER genes (XPA, XPC, XPD, XPE, XPF, XPG) cause **Xeroderma Pigmentosum (XP)**, characterized by extreme UV sensitivity, early-onset skin cancers, and neurodegeneration [cite:Molecular Biology of the Cell Ch 5]. ### Why Thymine Dimers Are Most Common 1. **Photochemistry:** Pyrimidines (especially thymine) have high UV absorption cross-sections 2. **Structural context:** Adjacent pyrimidines on the same strand are geometrically favorable for dimer formation 3. **Frequency in genome:** Thymine is abundant in DNA; TT and TC dinucleotides are common ### Clinical Correlation **Clinical Pearl:** Patients with XP who cannot repair thymine dimers develop skin cancers at rates 1000–10,000 times higher than the general population, often before age 20 [cite:Harrison 21e Ch 87]. ### Distinction from Other Lesions - **Depurination:** Spontaneous loss of purine base; repaired by base excision repair (BER), not NER - **Double-strand breaks:** Caused by ionizing radiation; repaired by homologous recombination or NHEJ - **Oxidative modifications:** 8-oxoguanine and other oxidative lesions; repaired by BER **Key Point:** While other DNA lesions occur, thymine dimers are the quantitatively dominant and most characteristic lesion from UV exposure, making them the most common substrate for NER.