Effective intra‐S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines |
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| Authors: | Marila Cordeiro‐Stone John J McNulty Christopher D Sproul Paul D Chastain Eugene Gibbs‐Flournoy Yingchun Zhou Craig Carson Shangbang Rao David L Mitchell Dennis A Simpson Nancy E Thomas Joseph G Ibrahim William K Kaufmann |
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| Institution: | 1. Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA;2. Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA;3. Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA;4. Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, NC, USA;5. Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA;6. Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA;7. Science Park – Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA |
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| Abstract: | The objective of this study was to assess potential functional attenuation or inactivation of the intra‐S checkpoint during melanoma development. Proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines were exposed to increasing fluences of UVC and intra‐S checkpoint responses were quantified. Melanocytes displayed stereotypic intra‐S checkpoint responses to UVC qualitatively and quantitatively equivalent to those previously demonstrated in skin fibroblasts. In comparison with fibroblasts, primary melanocytes displayed reduced UVC‐induced inhibition of DNA strand growth and enhanced degradation of p21Waf1 after UVC, suggestive of enhanced bypass of UVC‐induced DNA photoproducts. All nine melanoma cell lines examined, including those with activating mutations in BRAF or NRAS oncogenes, also displayed proficiency in activation of the intra‐S checkpoint in response to UVC irradiation. The results indicate that bypass of oncogene‐induced senescence during melanoma development was not associated with inactivation of the intra‐S checkpoint response to UVC‐induced DNA replication stress. |
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| Keywords: | human melanocyte melanoma DNA replication ultraviolet radiation replicon initiation intra‐S checkpoint |
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