title: Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency.
abstract: Ultraviolet (UV) radiation induces cyclobutane pyrimidine dimers (CPDs) and (6-4) photoproducts (6-4PPs) in DNA, which through gene mutations (e.g. in P53) may lead to skin carcinogenesis. Upon chronic low-level UV exposure, certain basal cells in mouse epidermis were reported to accumulate CPDs. These observations raised questions on whether these cells were fully DNA-repair deficient, and whether they were stem or progenitor cells, as suggested by their long residence time. We found that CPD-retaining basal cells (CRBCs) in SKH-1 hairless mice were repair proficient as accumulation of (6-4)PP, which is a hallmark for complete nucleotide excision repair-deficiency in rodents, was not observed. Accumulation of 6-4PP as well as CPD did, however, occur in basal cells in the epidermis of DNA repair-deficient Xpc-/- mice. Chronic UV exposure of DDB2 transgenic mice and DDB2 knockout mice revealed that the occurrence of CRBCs was inversely correlated with DDB2-expression, indicating that a boost in DNA repair lowered CPD accumulation. Stem cells are quiescent cells and can be identified as 5-bromo-2'-deoxyuridine-label retaining cells (BrdU-LRCs). Induction of BrdU-LRCs followed by chronic UV irradiation showed that all BrdU-label retaining stem cells were also CPD-retaining cells. As most CRBCs were not BrdU-labeled we surmized that these cells must include BrdU-negative stem cells and early progenitor cells. In confirmation of the latter, we found that CRBCs occurred among MTS24+ hair follicle progenitor cells. These findings provide the first evidence that epidermal stem and progenitor cells are prone to the accumulation of UV-induced DNA-damage and can be a prominent target in skin carcinogenesis.
authors.affiliation: Department of Dermatology, Leiden University Medical Center, PO Box 9600, 2300 RC, Leiden, The Netherlands. J.G.W.Nijhof@LUMC.nl
authors.forename: Joanne G W
authors.initials: JG
authors.lastname: Nijhof
authors.forename: Carina
authors.initials: C
authors.lastname: van Pelt
authors.forename: Adriaan A
authors.initials: AA
authors.lastname: Mulder
authors.forename: David L
authors.initials: DL
authors.lastname: Mitchell
authors.forename: Leon H F
authors.initials: LH
authors.lastname: Mullenders
authors.forename: Frank R
authors.initials: FR
authors.lastname: de Gruijl
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000235:genetics / Q000502:physiology; D001973:Bromodeoxyuridine; D004249:DNA Damage / Q000528:radiation effects*; D004260:DNA Repair / Q000502:physiology / Q000528:radiation effects*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D000078404:Epidermal Cells; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D006801:Humans; D008562:Membrane Glycoproteins / Q000235:genetics / Q000502:physiology; D051379:Mice; D008812:Mice, Hairless; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018462:Photobiology; D011740:Pyrimidine Dimers / Q000528:radiation effects*; D011836:Radiation Tolerance; D012878:Skin Neoplasms / Q000209:etiology; D013234:Stem Cells / Q000528:radiation effects*; D016159:Tumor Suppressor Protein p53; D014466:Ultraviolet Rays
chemical_list: D000954:Antigens, Surface; C117669:DDB2 protein, human; D004268:DNA-Binding Proteins; C496850:Ddb2 protein, mouse; D008562:Membrane Glycoproteins; C514060:Mts24 protein, mouse; D011740:Pyrimidine Dimers; D016159:Tumor Suppressor Protein p53; C501002:Xpc protein, mouse; C058406:pyrimidine-pyrimidone dimer; D001973:Bromodeoxyuridine