Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 102, Issue 52, Pages 18980-18985Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.0505505102
Keywords
cell-cycle arrest; differentiation; epidermis; turnover
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The interplay among nucleotide excision repair, cell-cycle regulation, and apoptosis in the UV-exposed epidermis is extremely important to avoid mutations and malignant transformation. In Xpc(-/-) mice deficient in global genome nucleotide excision repair (GGR), a cell-cycle arrest of epidermal cells in late S-phase [with near-double normal diploid (4N) DNA content] was observed 48-72 h after UV exposure. This arrest resolved without apoptosis (96168 h). We surmised that these arrested keratinocytes with persistent DNA damage were removed by epidermal turnover. In vivo BrdUrd pulse-chase labeling (> 17 h after UV exposure) showed that DNA replication after UV exposure was resumed in Xpc(-/-)mice, but it did not reveal any evidence of retained BrdUrd-labeled S-phase cells in the basal layer of the epidermis at 72 h. Interestingly, by this time a maximum number of cytokeratin 10-negative and cytokeratin 5-positive cells had appeared in the suprabasal epidermal cell layers of UV-exposed Xpc(-/-) mice. Accumulation of these basal cell-like keratinocytes in the suprabasal layers was clearly aberrant and was not observed in WT and heterozygous mice. Flow cytometric analyses of single-cell suspensions from UV-exposed Xpc(-/-) epidermis further showed that the near-4N arrested cells retained cytokeratin 5 and lacked cytokeratin 10. Hence, we conclude that the arrested near-4N cells became detached from the basal layer without entering a proper differentiation program and were indeed subsequently lost through the epidermal turnover. This expulsion apparently constitutes an alternative route, different from in situ apoptosis, to eliminate DNA-damaged arrested cells from the epidermis.
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