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Carcinogenesis Advance Access published online on November 24, 2006
Carcinogenesis, doi:10.1093/carcin/bgl213
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© The Author 2006. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org
Received September 4, 2006
Revised October 17, 2006
Accepted October 24, 2006

CANCER BIOLOGY

Epidermal stem and progenitor cells in murine epidermis accumulate UV damage despite NER proficiency

Joanne G.W. Nijhof 1 *, Carina van Pelt 1, Adriaan A. Mulder 1, David L. Mitchell 2, Leon H.F. Mullenders 3, and Frank R. de Gruijl 1

1 From the Department of Dermatology, Leiden University Medical Center, Leiden, The Netherlands
2 M.D. Anderson Cancer Center, Smithville, Tx, USA
3 From the Department of Toxicogenetics, Leiden University Medical Center, Leiden, The Netherlands

* To whom correspondence should be addressed.
Joanne G.W. Nijhof, E-mail: J.G.W.Nijhof{at}LUMC.nl


  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 NER-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 BrdU-label retaining cells (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-labelled we surmised 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.


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