Xeroderma pigmentosum is a human disease that results from defects in DNA repair

(Ken Greer/Visuals Unlimited.)

lead to increased rates of mutation. This concept is discussed further in Chapter 21.

Among the best studied of the human DNA repair diseases is xeroderma pigmentosum (Figure 17.31), 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 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. Although human cells lack photolyase (the enzyme that repairs pyrimidine dimers in bacteria), most pyrimi-dine 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 go uncorrected and may lead to cancer.

Xeroderma pigmentosum can result from defects in several different genes; studies have identified at least seven different xeroderma pigmentosum complementation groups, meaning that at least seven genes are required for nucleotide-excision repair in humans. Recent molecular research has led to the identification of genetic defects of nucleotide-excision repair associated with these complementation groups. Some persons with xeroderma pigmen-tosum have mutations in a gene encoding the protein that recognizes and binds to damaged DNA; others have mutations in a gene encoding helicase. Still others have defects in the genes that play a role in cutting the damaged strand on the 5' or 3' sides of the pyrimidine dimer. Some persons have a slightly different form of the disease (xeroderma pig-mentosum variant) owing to mutations in the gene encoding polymerase the DNA polymerase that bypasses pyrimidine dimers by inserting AA.

Two other genetic diseases due to defects in nucleotide-excision repair are Cockayne syndrome and trichothiodys-trophy (also known as brittle-hair syndrome). Persons who have either of these diseases do not have an increased risk of cancer but do exhibit multiple developmental and neurological problems. Both diseases result from mutations in some of the same genes that cause xeroderma pigmento-sum. Several of the genes taking part in nucleotide-excision repair produce proteins that also play a role in recombination and the initiation of transcription. These other functions may account for the developmental symptoms seen in Cockayne syndrome and trichothiodystrophy.

Another genetic disease caused by faulty DNA repair is an inherited form of colon cancer called hereditary non-polyposis colon cancer (HNPCC). This cancer is one of the most common hereditary cancers, accounting for about 15% of colon cancers. Research indicate that HNPCC arises from mutations in the proteins that carry out mismatch repair (see Figure 17.27).

Li-Fraumeni syndrome is caused by mutations in a gene called p53, which plays an important role in regulating the cell cycle. The product encoded by the p53 gene can halt cell division until damage to DNA has been repaired; it can also directly stimulate DNA repair. The p53 gene product may actually cause cells with damaged DNA to self-destruct (undergo apoptosis, or controlled cell death; see Chapter 21), preventing their mutated genetic instructions from being passed on. Patients who have Li-Fraumeni syndrome exhibit multiple independent cancers in different tissues. Some additional genetic diseases associated with defective

DNA repair are summarized in Table 17.6. __

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