Enhanced repair of cyclobutane pyrimidine dimers and improved UV resistance in photolyase transgenic mice.
During evolution, placental mammals appear to have lost cyclobutane pyrimidine dimer (CPD) photolyase, an enzyme that efficiently removes UV-induced CPDs from DNA in a light-dependent manner. As a consequence, they have to rely solely on the more complex, and for this lesion less efficient, nucleotide excision repair pathway. To assess the contribution of poor repair of CPDs to various biological effects of UV, we generated mice expressing a marsupial CPD photolyase transgene. Expression from the ubiquitous beta-actin promoter allowed rapid repair of CPDs in epidermis and dermis. UV-exposed cultured dermal fibroblasts from these mice displayed superior survival when treated with photoreactivating light. Moreover, photoreactivation of CPDs in intact skin dramatically reduced acute UV effects like erythema (sunburn), hyperplasia and apoptosis. Mice expressing the photolyase from keratin 14 promoter photo reactivate CPDs in basal and early differentiating keratinocytes only. Strikingly, in these animals, the anti-apoptotic effect appears to extend to other skin compartments, suggesting the presence of intercellular apoptotic signals. Thus, providing mice with CPD photolyase significantly improves repair and uncovers the biological effects of CPD lesions.
Schul
Wouter
W
MGC, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Rotterdam, PO Box 1738, 3000 DR Rotterdam, The Netherlands.
Jans
Judith
J
Rijksen
Yvonne M A
YM
Klemann
Kyra H M
KH
Eker
Andre P M
AP
de Wit
Jan
J
Nikaido
Osamu
O
Nakajima
Satoshi
S
Yasui
Akira
A
Hoeijmakers
Jan H J
JH
van der Horst
Gijsbertus T J
GT
D000199:Actins / Q000235:genetics; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002478:Cells, Cultured / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics*; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000235:genetics / Q000502:physiology*; D004817:Epidermis / Q000473:pathology / Q000528:radiation effects; D004890:Erythema / Q000209:etiology / Q000517:prevention & control; D005347:Fibroblasts / Q000528:radiation effects; D005982:Glutathione Transferase / Q000235:genetics; D006801:Humans; D006965:Hyperplasia; D015603:Keratinocytes / Q000378:metabolism / Q000528:radiation effects; D007633:Keratins / Q000235:genetics; D007614:Macropodidae / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D011401:Promoter Regions, Genetic; D011740:Pyrimidine Dimers / Q000378:metabolism*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control; D011836:Radiation Tolerance / Q000235:genetics*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D012867:Skin / Q000473:pathology / Q000528:radiation effects; D019076:Transgenes; D014466:Ultraviolet Rays
D000199:Actins; D011740:Pyrimidine Dimers; D011993:Recombinant Fusion Proteins; D007633:Keratins; D004247:DNA; D005982:Glutathione Transferase; D004255:Deoxyribodipyrimidine Photo-Lyase