Xeroderma pigmentosum: clues to understanding cancer initiation

Abstract Xeroderma pigmentosum (XP) type C is a rare autosomal recessive disorder that occurs because of inactivation of the xeroderma pigmentosum group C (XPC) protein, which is an important DNA damage recognition protein involved in DNA nucleotide excision repair (NER). This defect, which prevents removal of a wide array of direct and indirect DNA lesions, is associated with a decrease in catalase activity. As a novel photoprotective approach, lentivirus-mediated catalase overexpression in XPC human keratinocytes results in a marked decrease in sunburn cell formation, caspase-3 activation, and p53 accumulation following UVB irradiation. While not correcting the gene defect, indirect gene therapy using antioxidant enzymes may be helpful in limiting photosensitivity in XP type C, as well as in other monogenic/polygenic photosensitive disorders characterized by reactive oxygen species (ROS) accumulation. Hypoxia-inducible factor-1 (HIF-1), a major transcription factor sensitive to oxygen levels, responds to various stress factors. As a common stressor of skin, UVB induces a biphasic HIF-1a variation through ROS generation in keratinocytes. HIF-1a has an important regulator effect on the expression of XPC protein and other NER genes, indicating indirect regulation of NER by ROS. The intrinsic genomic instability arising in XP type C provides a good opportunity to investigate the complex molecular mechanisms underlying the Warburg effect (the shift of mito-chondrial metabolism towards glycolysis). Overall, the monogenic disorder XP type C is a powerful tool for studying photoprotection and cancer.