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 (96 -168 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.cell-cycle arrest ͉ differentiation ͉ epidermis ͉ turnover