Carcinogenesis Advance Access originally published online on November 24, 2006
Carcinogenesis 2007 28(4):792-800; doi:10.1093/carcin/bgl213
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Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency
1 Department of Dermatology, Leiden University Medical Center PO Box 9600, 2300 RC, Leiden, The Netherlands
2 Department of Toxicogenetics, Leiden University Medical Center PO Box 9600, 2300 RC, Leiden, The Netherlands
3 M.D. Anderson Cancer Center Smithville, TX, USA
*To whom correspondence should be addressed. Tel: +31 715269363; Fax: +31 715268286; Email: J.G.W.Nijhof{at}LUMC.nl
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.
Abbreviations: BrdU-LRC, 5-bromo-2'-deoxyuridine-label-retaining cell; CPD, cyclobutane pyrimidine dimer; CRBCs, CPD-retaining basal cells; DDB, damaged DNA binding protein; GG-NER, global genome NER; MED, minimal erythema dose; NER, nucleotide excision repair; (6-4)PPs, (6-4) pyrimidine pirimidone photoproducts; RT, room temperature; SEM, standard error of the mean; TCR, transcription coupled repair; UVB, ultraviolet B; XPC, xeroderma pigmentosum C
Received September 4, 2006; revised October 17, 2006; accepted October 24, 2006.