Repair of UV-induced thymine dimers is compromised in cells expressing the E6 protein from human papillomaviruses types 5 and 18

On a worldwide basis, nonmelanoma skin cancers (NMSCs) are the most commonly diagnosed cancers amongst Caucasians (de Villiers et al, 1999; Kiviat, 1999). The major contributing factor to the development of NMSCs at sun-exposed sites is through DNA damage caused by ultraviolet radiation (UVR). The importance of effective DNA damage repair is highlighted by studies on patients affected with the inherited disease Xeroderma pigmentosum (XP), who are at greatly increased risk of developing NMSCs at sun-exposed body sites (Ellis, 1997). This propensity is due to disabling mutations in the XP genes, which are involved in the repair of DNA damage via the nucleotide excision repair (NER) pathway. A similar susceptibility to develop NMSCs is observed in patients with the rare genetic disease epidermodysplasia verruciformis (EV) (Orth, 1986), which predisposes to infection with a particular class of HPV (EV-HPV). In EV-patients, skin tumours are found at sun-exposed sites and appear to associate with and arise from HPV-infected lesions. This suggests that EV-HPV types, principally types 5 and 8, may have a role in promoting the tumorigenic process. Likewise, renal transplant recipients (RTRs), who also are subject to extensive HPV-verrucosis, display an increased risk of developing NMSCs at sun-exposed sites (Surentheran et al, 1998; Harwood et al, 2000), with the tumours arising from wart sites. Overall, these clinical data suggest that, in addition to UV-radiation, HPV infections may contribute towards the appearance of NMSCs at sun-exposed sites. Recently, it has been observed that cells expressing the HPV E6 protein of type 16, which can promote the degradation of the tumour suppressor p53, also display reduced ability to repair DNA damage (El-Mahdy et al, 2000). As the repair of UV damage is, at least in part, dependent on the p53 status of the cells (Ford and Hanawalt, 1995, 1997), the failure to repair DNA damage effectively may be due to the cells being functionally p53 null.