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What DNA repair system is missing in most cases of xeroderma pigmentosum? Why does that make XP patients so sensitive to UV light? What is the primary backup system for these patients?
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The DNA repair system that is missing in most cases of xeroderma pigmentosum is the nucleotide excision repair (NER) system. Show more…
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The condition known as xeroderma pigmentosum (XP) arises from mutations in at least seven different human genes (see Box $25-1$ ). The deficiencies are generally in genes encoding enzymes involved in some part of the pathway for human nucleotide-excision repair. The various types of XP are denoted A through G (XPA, XPB, etc.), with a few additional variants lumped under the label XP-V. Cultures of fibroblasts from healthy individuals and from patients with XPG are irradiated with ultraviolet light. The DNA is isolated and denatured, and the resulting single-stranded DNA is characterized by analytical ultracentrifugation. (a) Samples from the normal fibroblasts show a significant reduction in the average molecular weight of the single-stranded DNA after irradiation, but samples from the XPG fibroblasts show no such reduction. Why might this be? (b) If you assume that a nucleotide-excision repair system is operative in fibroblasts, which step might be defective in the cells from the patients with XPG? Explain.
Humans with the rare genetic disease Xeroderma Pigmentosum (XP) are extremely sensitive to sunlight and prone to developing malignant skin cancers. Defects in any of the eight genes cause XP. Seven XP genes encode proteins involved in nucleotide excision repair (NER). The eighth gene is associated with the XP variant XP-V form of the disease. Cells from XP-V patients are proficient for NER but do not accurately replicate UV damaged DNA. Using a clever assay, you manage to purify from a normal cell extract the enzyme that is missing from XP-V cells. You test its ability to synthesize DNA from the simple template in Fig 1a, which contains a TT sequence. This template can be modified to contain either a cyclobutane thymine dimer or the somewhat rare 6-4 photoproduct (two Ts linked in a different way). You compare the ability of DNA pol alpha (normal replicative pol) and XP-V enzyme to synthesize DNA from the undamaged template, the template with a cyclobutane dimer, and the template with a 6-4 photoproduct. By labeling the primer at its 5' end and denaturing the reaction products, it is possible to determine whether DNA synthesis has occurred (Fig 1B). A. Is the XP-V enzyme a DNA pol? Why or why not? B. How does the XP-V enzyme differ from DNA pol alpha on an undamaged template? On a template with a cyclobutane dimer? On a template with a 6-4 photoproduct? C. How accurately do you suppose that the XP-V enzyme copies normal DNA? Would you guess it to be error-prone or faithful? D. If Nucleotide Excision Repair (NER) is normal in patients with XP-V, why are they sensitive to sunlight and prone to skin cancers?
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