Genetic Diseases and Faulty DNA Repair

Several human diseases are connected to defects in DNA repair. These diseases are often associated with high incidences of specific cancers because defects in DNA repair lead to increased rates of mutation. This phenomenon is discussed further in Chapter 16.

Among the best-studied of the human DNA-repair diseases is xeroderma pigmentosum (Figure 13.28), a rare autosomal recessive condition that includes abnormal skin pigmentation and acute sensitivity to sunlight. Persons who have this disease also have a strong predisposition to skin cancer, with an incidence ranging from 1000 to 2000 times that found in unaffected people. Sunlight includes a strong UV component, so exposure to sunlight produces pyrimidine dimers in the DNA of skin cells. Most pyrimidine dimers in humans can be corrected by nucleotide-excision repair. However, the cells of most people with xeroderma pigmentosum are defective in nucleotide-excision repair, and many of their pyrimidine dimers remain uncorrected and may lead to cancer.

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Figure 13.28: Xeroderma pigmentosum results from defects in DNA repair. The disease is characterized by freckle-like spots on the skin (shown here) and a predisposition to skin cancer.
[Stephane AUDRAS/REA/Redux.]

Another genetic disease caused by faulty DNA repair is an inherited form of colon cancer called hereditary nonpolyposis colon cancer (HNPCC). It is one of the most common hereditary cancers, accounting for about 15% of colon cancers. Research findings indicate that HNPCC arises from mutations in the proteins that carry out mismatch repair. Some genetic diseases associated with defective DNA repair are summarized in Table 13.4. image TRY PROBLEM 27

TABLE 13.4 Genetic diseases associated with defects in DNA-repair systems
Disease Symptoms Genetic defect
Xeroderma pigmentosum Freckle-like spots on skin, sensitivity to sunlight, predisposition to skin cancer Defects in nucleotide-excision repair
Cockayne syndrome Dwarfism, sensitivity to sunlight, premature aging, deafness, intellectual disability Defects in nucleotide-excision repair
Trichothiodystrophy Brittle hair, skin abnormalities, short stature, immature sexual development, characteristic facial features Defects in nucleotide-excision repair
Hereditary nonpolyposis colon cancer Predisposition to colon cancer Defects in mismatch repair
Fanconi anemia Increased skin pigmentation, abnormalities of skeleton, heart, and kidneys, predisposition to leukemia Possibly defects in the repair of inter-strand cross-links
Li–Fraumeni syndrome Predisposition to cancer in many different tissues Defects in DNA damage response
Werner syndrome Premature aging, predisposition to cancer Defect in homologous recombination

CONCEPTS

Defects in DNA repair are the underlying cause of several genetic diseases. Many of these diseases are characterized by a predisposition to cancer.

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Why are defects in DNA repair often associated with increases in cancer?

Changes in DNA structure may not undergo repair in people with defects in DNA-repair mechanisms. Consequently, increased numbers of mutations occur at all genes, including those that predispose to cancer. This observation indicates that cancer arises from mutations in DNA.