A 7-month-old boy presents to the family physician with extensive scaliness and pigmentation of sun-exposed skin areas. His mother says that these symptoms were absent until mid-spring and then became significantly worse after their trip to California in the summer. The child was born in December to a consanguineous couple after an uncomplicated pregnancy. He is breastfed and receives mashed potatoes, bananas, and carrots as complementary foods. His weight is 8.5 kg (18.7 lb) and length is 70 cm (2 ft 96 in). The patient’s vital signs are within normal limits for his age. On physical examination, there is freckling, scaling, and erythema on the sunlight-exposed areas of the face, trunk, and upper and lower extremities. No blistering, scarring, hypertrichosis, or alopecia is noted. The rest of the exam is unremarkable. Which process is most likely disrupted in this patient?

Hydroxylation of proline and lysine in the procollagen molecule

Conversion of uroporphyrinogen III to coproporphyrinogen III

While performing a Western blot, a graduate student spilled a small amount of the radiolabeled antibody on her left forearm. Although very little harm was done to the skin, the radiation did cause minor damage to the DNA of the exposed skin by severing covalent bonds between the nitrogenous bases and the deoxyribose sugar, leaving several apurinic/apyrimidinic sites. Damaged cells would most likely repair these sites by which of the following mechanisms?

Nonhomologous end joining repair

A 54-year-old woman with breast cancer comes to the physician because of redness and pain in the right breast. She has been undergoing ionizing radiation therapy daily for the past 2 weeks as adjuvant treatment for her breast cancer. Physical examination shows erythema, edema, and superficial desquamation of the skin along the right breast at the site of radiation. Sensation to light touch is intact. Which of the following is the primary mechanism of DNA repair responsible for preventing radiation-induced damage to neighboring neurons?

Nonhomologous end joining repair

An investigator studying DNA mutation mechanisms isolates single-stranded DNA from a recombinant bacteriophage and sequences it. The investigator then mixes it with a buffer solution and incubates the resulting mixture at 70°C for 16 hours. Subsequent DNA resequencing shows that 3.7 per 1,000 cytosine residues have mutated to uracil. Which of the following best describes the role of the enzyme that is responsible for the initial step in repairing these types of mutations in living cells?

Connecting the phosphodiester backbone

Cleavage of the phosphodiester bond 3' of damaged site

Release of the damaged nucleotide

Addition of free nucleotides to 3' end

Nucleotide excision repair — USMLE Lesson

NER Mechanism - The Bulky Patrol

Function: Repairs bulky DNA lesions that distort the double helix.
Examples: Thymine dimers (pyrimidine dimers) from UV light, damage from smoking (benzopyrene).

Mechanism:
- Recognition: Specific endonucleases recognize the bulky distortion.
- Excision: The enzyme complex cleaves the phosphodiester backbone on both sides of the lesion.
- Synthesis: DNA Polymerase I synthesizes new DNA using the undamaged strand as a template.
- Ligation: DNA Ligase seals the final nick.

⭐ High-Yield: NER is the primary pathway for removing UV-induced pyrimidine dimers, preventing skin cancers like melanoma.

📌 Mnemonic: Night Exposure Requires repair (for UV damage).

Xeroderma Pigmentosum - Sunlight's Enemy

Xeroderma Pigmentosum: Severe Freckling and Skin Changes

Pathophysiology: Defective Nucleotide Excision Repair (NER), leading to an inability to repair DNA damage from UV light.
- Mechanism: Failure to excise pyrimidine dimers (especially thymine dimers) formed by UV radiation.
- Genetics: Autosomal recessive inheritance.
Clinical Presentation:
- Skin: Extreme photosensitivity from birth, severe sunburns, freckle-like lesions, and premature skin aging. Skin becomes dry and parchment-like (xeroderma).
- Ocular: Photophobia, conjunctivitis, keratitis, and eyelid atrophy.
- Neurologic: Occurs in ~25% of patients; includes sensorineural hearing loss and progressive neurodegeneration.

⭐ Patients have a >1000-fold increased risk of developing basal cell carcinoma, squamous cell carcinoma, and melanoma, typically before age 20.

Cockayne Syndrome - A Different Defect

Core Defect: Impaired transcription-coupled nucleotide excision repair (TC-NER), essential for fixing DNA lesions in actively transcribed genes. Caused by mutations in ERCC6 (CSB) or ERCC8 (CSA).
Clinical Hallmarks:
- Photosensitivity without pigmentation changes.
- Progeria: premature aging signs.
- Severe neurodegeneration, cachectic dwarfism.
- "Bird-like" facies, optic atrophy, deafness.

⭐ Key Distinctor: Unlike Xeroderma Pigmentosum, patients with Cockayne Syndrome do not have an increased predisposition to skin cancer, as global NER remains functional.

High‑Yield Points - ⚡ Biggest Takeaways

Nucleotide Excision Repair (NER) corrects bulky, helix-distorting lesions like pyrimidine dimers from UV light and large chemical adducts.

It is the only pathway to repair pyrimidine dimers in humans.

The core process is a "cut and patch" mechanism where excinucleases remove a segment of the damaged strand.

Defects in NER lead to Xeroderma Pigmentosum (XP), presenting with extreme sun sensitivity and a vastly increased risk of skin cancer.

Unlock the full lesson and continue reading

Signup to continue reading this lesson and unlimited access questions, flashcards, AI notes, and more

Scan to download app

UNLOCK FREE ACCESS