Journal Article

Accelerated elimination of ultraviolet-induced DNA damage through apoptosis in CDC25A-deficient skin

Jodi Yanagida, Brianna Hammiller, Jenan Al-Matouq, Michaela Behrens, Carol S. Trempus, Susan K. Repertinger and Laura A. Hansen

in Carcinogenesis

Volume 33, issue 9, pages 1754-1761
Published in print September 2012 | ISSN: 0143-3334
Published online July 2012 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgs168
Accelerated elimination of ultraviolet-induced DNA damage through apoptosis in CDC25A-deficient skin

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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.

Abbreviations:

8-oxo-dG

8-oxo-deoxyguanosine

ATR

ataxia telangiectasia and Rad3-related

BrdU

bromodeoxyuridine

CDC25A

cell division cycle 25A

CDK2

cyclin-dependent kinase 2

CPD

cyclopyrimidine

DAPI

4ʹ,6-diamidino-2 phenylindole

TBS-T

Tris-buffered saline Tween 20

TUNEL

terminal dUTP nucleotide end-labeling

UV

ultraviolet

Journal Article.  5986 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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