Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency
| Autor: | Joanne G.W. Nijhof, Adriaan A. Mulder, Frank R. de Gruijl, Leon H.F. Mullenders, Carina van Pelt, David L. Mitchell |
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| Rok vydání: | 2006 |
| Předmět: |
Cancer Research
Skin Neoplasms DNA Repair Ultraviolet Rays DNA repair Mice Transgenic Pyrimidine dimer Biology Gene mutation medicine.disease_cause Radiation Tolerance Mice medicine Animals Humans Progenitor cell Mice Knockout Genetics Mice Hairless Membrane Glycoproteins Epidermis (botany) Stem Cells General Medicine Fibroblasts Hair follicle Photobiology Cell biology DNA-Binding Proteins medicine.anatomical_structure Bromodeoxyuridine Epidermal Cells Pyrimidine Dimers Antigens Surface Tumor Suppressor Protein p53 Stem cell Carcinogenesis DNA Damage |
| Zdroj: | Carcinogenesis. 28:792-800 |
| ISSN: | 1460-2180 0143-3334 |
| DOI: | 10.1093/carcin/bgl213 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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