biostudies-literatureCordeiro-Stone MCurriculum in ToxicologyNIEHS NIH HHSEnvironmental PathologyU.S. Public Health ServiceNCI NIH HHS68-80https://www.ebi.ac.uk/biostudies/studies/S-EPMC4745347biostudies-literatureUnknown29(1)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.Pigment cell & melanoma researchEffective intra-S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines.PMC4745347P30-CA16086P30 CA016086T32 ES007126T32 ES007017P30 ES10126P01 ES014635P30 ES010126RO1 ES015856R01 ES015856Rao SSimpson DAMcNulty JJMitchell DLCordeiro-Stone MZhou YGibbs-Flournoy EIbrahim JGChastain PDSproul CDKaufmann WKCarson CThomas NEfalseEffective intra-S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines.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.2016-01-01T00:00:00Z2016 Jan2024-11-09T15:54:35.079Z2019-03-27T02:08:42ZS-EPMC47453472643700510.1111/pcmr.12426