Box 3 | Xeroderma pigmentosum 

Xeroderma pigmentosum (XP)^{1, 51-53, 87, 89} is a disease that is inherited strictly in an autosomal-recessive mode. XP has a worldwide distribution. The incidence varies from about 1 in 250,000 in Western countries to as high as 1 in 40,000 in Japan. Although the severity varies in different patients, cutaneous symptoms such as marked skin burning on minimal sun exposure can be detected as early as the first sun exposure within weeks of birth. The eyelids, conjunctiva and cornea are frequently affected because of ultraviolet radiation exposure, especially in very sunny climates. Oral abnormalities also occur for similar reasons. Even the tip of the tongue may show signs of sun damage. The estimated incidence of cutaneous basal cell carcinoma and squamous cell carcinoma is elevated more than 1000-fold in individuals with XP under 20 years of age and is elevated more than 100,000-fold for squamous cell carcinoma of the tip of the tongue. An association of the cutaneous manifestations of XP with various neurological phenotypes is observed in about 20% of cases.

Individuals with XP have a high incidence of premalignant actinic keratoses (proliferative lesions in the skin, which signal impending neoplastic change), as well as benign and malignant skin tumours. The median age of onset of skin cancer is 8 years, nearly 50 years younger than in the general US population. This is the earliest onset of neoplasia documented for any recessive human hereditary disease and reflects the importance of DNA repair in the prevention of these cancers in the general population. Neoplasms are predominantly basal cell and squamous cell carcinomas of the skin, but also include melanomas, keratoacanthomas (tumours that arise from cells of the skin appendages, such as hair follicles), angiomas and sarcomas. The cutaneous features of XP are essentially identical in patients with XP-AXP-G, although XP-E patients tend to have milder symptoms and a later onset of cancer, and XP-C patients are less frequently afflicted neurologically.

The eighth genetic complementation group for XP is called XP-V (for the variant form of the disease)^{1, 51-53}. XP-V patients are clinically indistinguishable from those with classical XP, but are fully proficient for NER. This conundrum was recently solved when it was shown that the product of the XPV gene is an unusual DNA polymerase called DNA polymerase ^{54, 90}. This polymerase is highly error prone when copying normal DNA (the measured error rate is about 6,000 times higher than that of the high-fidelity polymerases involved in DNA replication)⁹¹. High-fidelity replicative DNA polymerases, however, cannot replicate through sites of base damage. By contrast, DNA polymerase can bypass such lesions, and does so by incorporating nucleotides opposite sites of base damage^{54, 90}. The error rate is less than 5%, so the generation of mutations is avoided most of the time. The specific catalytic attributes of an enzyme such as DNA polymerase that facilitates the correct reading of templates in which bases have an abnormal structure is an area of intense interest and research activity. (Figure adapted with permission from Ref. 51).

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