title: Accelerated elimination of ultraviolet-induced DNA damage through apoptosis in CDC25A-deficient skin.
abstract: Cell division cycle 25A (CDC25A) is a dual-specificity phosphatase that removes inhibitory phosphates from cyclin-dependent kinases, allowing cell-cycle progression. Activation of cell-cycle checkpoints following DNA damage results in the degradation of CDC25A, leading to cell-cycle arrest. Ultraviolet (UV) irradiation, which causes most skin cancer, results in both DNA damage and CDC25A degradation. We hypothesized that ablation of CDC25A in the skin would increase cell-cycle arrest following UV irradiation, allowing for improved repair of DNA damage and decreased tumorigenesis. Cdc25a(fl/fl) /Krt14-Cre recombinase mice, with decreased CDC25A in the epithelium of the skin, were generated and exposed to UV. UV-induced DNA damage, in the form of cyclopyrimidine dimers and 8-oxo-deoxyguanosine adducts, was eliminated earlier from CDC25A-deficient epidermis. Surprisingly, loss of CDC25A did not alter epidermal proliferation or cell cycle after UV exposure. However, the UV-induced apoptotic response was prolonged in CDC25A-deficient skin. Double labeling of cleaved caspase-3 and the DNA damage marker γH2A.X revealed many of the apoptotic cells in UV-exposed Cdc25a mutant skin had high levels of DNA damage. Induction of skin tumors by UV irradiation of Cdc25a mutant and control mice on a skin tumor susceptible to v-ras(Ha) Tg.AC mouse background revealed UV-induced papillomas in Cdc25a mutants were significantly smaller than in controls in the first 6 weeks following UV exposure, although there was no difference in tumor multiplicity or incidence. Thus, deletion of Cdc25a increased apoptosis and accelerated the elimination of DNA damage following UV but did not substantially alter cell-cycle regulation or tumorigenesis.
authors: Department of Biomedical Sciences, Creighton University School of Medicine, 2500 California Plaza Omaha, NE 68178, USA.
authors: Jodi
authors: J
authors: Yanagida
authors: Brianna
authors: B
authors: Hammiller
authors: Jenan
authors: J
authors: Al-Matouq
authors: Michaela
authors: M
authors: Behrens
authors: Carol S
authors: CS
authors: Trempus
authors: Susan K
authors: SK
authors: Repertinger
authors: Laura A
authors: LA
authors: Hansen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000528:radiation effects*; D002453:Cell Cycle; D049109:Cell Proliferation / Q000528:radiation effects; D004247:DNA / Q000528:radiation effects*; D004249:DNA Damage; D051379:Mice; D008810:Mice, Inbred C57BL; D012867:Skin / Q000473:pathology / Q000528:radiation effects*; D014466:Ultraviolet Rays; D020687:cdc25 Phosphatases / Q000172:deficiency / Q000502:physiology*
chemical_list: D004247:DNA; C517005:Cdc25a protein, mouse; D020687:cdc25 Phosphatases