Photoreactivation in humans.

Photoreactivation is a DNA repair pathway that requires the presence of a photoreactivating enzyme, DNA photolyase. DNA photolyase recognizes and binds specifically to ultraviolet radiation (UVR)-induced cyclobutane pyrimidine dimers in DNA. Exposure of the photolyase-dimer complex to wavelengths in the range of 300-500 nm results, upon absorption of a photon, in the return of the dimerized pyrimidines to their monomeric form (1). While Kelner (2) is generally credited with the discovery of photoreactivation in 1949, a photoreactivation type of process was reported in 1933 by Hausser and von Oehmcke (see ref. 3), who observed that UVR-induced darkening of banana skin could be prevented by post-UVR exposure to nearUVR (366 nm) and visible light. Clear evidence for photoreactivation has been observed in numerous prokaryotes (3) and certain eukaryotes including fish (4) and marsupials (5). Evidence for photoreactivation in placental mammals is less convincing. Sutherland (6) reported in 1974 that DNA photolyase was present in human leukocytes. Since that time, photolyase has been reported to be present in human and murine cells in culture (7, 8) and in human skin (9, 10). The occurrence of photoreactivation in these studies was dependent upon the medium in which the cells were grown (7), the tissue from which extracts were prepared (9), and the manner in which the photoreactivation treatments were administered-i.e., no photoreactivation was observed following a single exposure to UVR and subsequent visible light, but 40% removal of dimers was measured following three cycles of UVR/visible light given at 2.5-hr intervals (10). In the marsupial Monodelphis domestica, removal of pyrimidine dimers by photoreactivation is readily demonstrated. The process of photoreactivation in M. domestica appears to occur in all tissues (11-13) and with a wide variety of photoreactivation protocols (unpublished observations). Attempts to measure the capacity of photoreactivation to suppress UVR-induced injury to human skin have yielded unimpressive results. As regards erythema induction in man, post-UVR exposure to longer wavelengths of light has been reported to enhance erythema induction (14) or to have a mild (15) or small (16) effect on prevention of erythema. On the other hand, photoreactivation in M. domestica clearly reduced the severity of such UVR-induced pathologic changes in the skin as erythema, edema, desquamation, hyperplasia, sunburn-cell formation and the appearance ofmelanotic and nonmelanotic tumors (17-19). In addition, photoreactivation reduced the incidence and severity of UVR-induced preneoplastic and neoplastic changes in the eyes of M. domestica (19, 20). If the same light-activated repair process found in marsupials occurs in human skin, why is it so difficult to demonstrate in humans cells in a reproducible manner? Recent results from the laboratory of A. Sancar, published in this issue of the Proceedings (21), clearly indicate that photoreactivation is either missing or of no practical significance in human cells. This observation is of considerable importance as regards the significance, or potential significance, of photoreactivation to human health. If the same lightactivated repair pathway found in marsupials occurred consistently in human skin, the detrimental effects of human exposure to UVR could be readily diminished by post-UVR exposure to the appropriate light sources, either natural or artificial, that emit radiation in the wavelength range of 300-500 nm. Thus, photoreactivation might be expected to prevent sunburn and the appearance of nonmelanoma and melanoma skin cancer in humans. However, based on the evidence at hand, it seems unlikely at this time to think that photoreactivation could serve as an effective therapy for the prevention of pathological conditions in sun-exposed human skin. 1. Cook, J. S. (1970) Photophysiology 5, 191-223. 2. Kelner, A. (1949) Proc. Natl. Acad. Sci. USA 35, 73-79. 3. Jagger, J. (1960) Radiation Protection and Recovery (Pergamon, Oxford), pp. 352-377. 4. Shima, A., Ikenaga, O., Nikaido, H., Takebe, H. & Egami, N. (1981) Photochem. Photobiol. 33, 313-316. 5. Cook, J. S. & Regan, J. D. (1969) Nature (London) 233, 1066-1067. 6. Sutherland, B. M. (1974) Nature (London) 248, 109-112. 7. Sutherland, B. M. & Oliver, R. (1976) Biochim. Biophys. Acta 442, 358-367. 8. Sutherland, B. M., Runge, P. & Sutherland, J. C. (1974) Biochemistry 13, 47104715. 9. Ogut, S. E., D'Ambrosio, S. M., Samuel, M. & Sutherland, B. M. (1989) J. Photochem. Photobiol. B Biol. 4, 47-56. 10. Roza, L., De Gruijl, F. R., Bergen Henegouwen, J. B. A., Guikers, K., Van Weelden, H., Van der Schans, P. & Baan, R. A. (1991) J. Invest. Dermatol. 96, 903-907. 11. Sabourin, C. L. K. & Ley, R. D. (1988) Photochem. Photobiol. 47, 719-723. 12. Ley, R. D. (1984) Photochem. Photobiol. 40, 141-143. 13. Ley, R. D., Applegate, L. A. & Freeman, S. E. (1988) Mutat. Res. 194, 4955. 14. Willis, I., Kligman, A. M. & Epstein, J. H. (1973) J. Invest. Dermatol. 59, 416-420. 15. Paul, B. S. & Parrish, J. A. (1982) J. Invest. Dermatol. 78, 371-374. 16. Van Weelden, H. & van der Leun, J. C. (1986) in The Biological Effects of UVA Radiation, eds. Urbach, F. & Gange, R. W. (Praeger, New York), pp. 147-152. 17. Ley, R. D. & Applegate, L. A. (1989) in Models in Dermatology, eds. Maibach, H. I. & Lowe, N. J. (Karger, Basel), pp. 265-275. 18. Ley, R. D., Applegate, L. A., Padilla, R. S. & Stuart, T. D. (1989) Photochem. Photobiol. 50, 1-5. 19. Ley, R. D., Applegate, L. A., Fry, R. J. M. & Sanchez, A. B. (1991) Cancer Res. 51, 6539-6542. 20. Applegate, L. A. & Ley, R. D. (1991) Exp. Eye Res. 52, 493-497. 21. Li, Y. F., Kim, S.-T. & Sancar, A. (1993) Proc. Natl. Acad. Sci. USA 90, 43894393.