title: Differential role of basal keratinocytes in UV-induced immunosuppression and skin cancer.
abstract: Cyclobutane pyrimidine dimers (CPDs) and 6-4 photoproducts (6-4PPs) comprise major UV-induced photolesions. If left unrepaired, these lesions can induce mutations and skin cancer, which is facilitated by UV-induced immunosuppression. Yet the contribution of lesion and cell type specificity to the harmful biological effects of UV exposure remains currently unclear. Using a series of photolyase-transgenic mice to ubiquitously remove either CPDs or 6-4PPs from all cells in the mouse skin or selectively from basal keratinocytes, we show that the majority of UV-induced acute effects to require the presence of CPDs in basal keratinocytes in the mouse skin. At the fundamental level of gene expression, CPDs induce the expression of genes associated with repair and recombinational processing of DNA damage, as well as apoptosis and a response to stress. At the organismal level, photolyase-mediated removal of CPDs, but not 6-4PPs, from the genome of only basal keratinocytes substantially diminishes the incidence of skin tumors; however, it does not affect the UVB-mediated immunosuppression. Taken together, these findings reveal a differential role of basal keratinocytes in these processes, providing novel insights into the skin's acute and chronic responses to UV in a lesion- and cell-type-specific manner.
authors.affiliation: MGC, Department of Cell Biology and Genetics, Center for Biomedical Genetics, Erasmus University Medical Center, 3000 DR Rotterdam, The Netherlands.
authors.forename: Judith
authors.initials: J
authors.lastname: Jans
authors.forename: George A
authors.initials: GA
authors.lastname: Garinis
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Adri
authors.initials: A
authors.lastname: van Oudenaren
authors.forename: Michael
authors.initials: M
authors.lastname: Moorhouse
authors.forename: Marcel
authors.initials: M
authors.lastname: Smid
authors.forename: Yurda-Gul
authors.initials: YG
authors.lastname: Sert
authors.forename: Albertina
authors.initials: A
authors.lastname: van der Velde
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Rijksen
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van der Spek
authors.forename: Akira
authors.initials: A
authors.lastname: Yasui
authors.forename: Jan H J
authors.initials: JH
authors.lastname: Hoeijmakers
authors.forename: Pieter J M
authors.initials: PJ
authors.lastname: Leenen
authors.forename: Gijsbertus T J
authors.initials: GT
authors.lastname: van der Horst
mesh_terms: D000818:Animals; D017209:Apoptosis; D002277:Carcinoma / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D002331:Carnitine / Q000031:analogs & derivatives / Q000235:genetics / Q000502:physiology; D016000:Cluster Analysis; D004255:Deoxyribodipyrimidine Photo-Lyase / Q000235:genetics / Q000378:metabolism*; D006965:Hyperplasia / Q000209:etiology; D007165:Immunosuppression Therapy / Q000379:methods*; D053547:Keratin-14 / Q000235:genetics; D015603:Keratinocytes / Q000473:pathology / Q000528:radiation effects*; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011740:Pyrimidine Dimers; D011836:Radiation Tolerance; D012867:Skin / Q000473:pathology* / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000235:genetics / Q000517:prevention & control; D014158:Transcription, Genetic; D014466:Ultraviolet Rays
chemical_list: D053547:Keratin-14; D011740:Pyrimidine Dimers; C058406:pyrimidine-pyrimidone dimer; C033107:cyclobutanecarbonylcarnitine; D004255:Deoxyribodipyrimidine Photo-Lyase; D002331:Carnitine