Biology Department Seminar

DNA damage is a significant cause of skin cancer, both because it leads to mutations in key tumor suppressor genes, and because it suppresses the immune system. This is emphasized in the genetic disease xeroderma pigmentosum, where a defect in one of eight DNA repair genes leads to drastically increased skin cancer incidence, even as children. New mouse models of XP show that the disease increases immune suppression following even very low doses of UV-B. The disease in people has been treated experimentally with topical T4N5 liposome lotion, which contains the DNA repair enzyme T4 endonuclease V encapsulated in liposomes. Clinical studies in these patients have shown a reduction skin cancer incidence. Studies with T4N5 liposome lotion have uncovered that UV-induced DNA damage causes the release of cytokines, such as TNFalpha, IL-1 and IL-10. Increasing DNA repair attenuates the release of these cytokines. DNA damage also causes the release of cytokines that trigger wrinkle formation. Studies with UV-irradiated mice show that increasing DNA repair with T4N5 liposome lotion reduces wrinkles. We now have experimental evidence that UV-induced DNA damage to keratinocytes in the epidermis causes release of soluble mediators that travel to undamaged fibroblasts, and trigger the release of MMP-1, one of the key proteases that contribute to wrinkle formation. These findings reveal that DNA damage to the upper layers of skin can indirectly cause the destruction of collagen and wrinkles in lower layers of skin. The conclusion is that DNA damage is a central mechanism of photoaging.