title: Effective intra-S checkpoint responses to UVC in primary human melanocytes and melanoma cell lines.
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.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.|Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Marila
authors.initials: M
authors.lastname: Cordeiro-Stone
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: John J
authors.initials: JJ
authors.lastname: McNulty
authors.affiliation: Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Sproul
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Paul D
authors.initials: PD
authors.lastname: Chastain
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Eugene
authors.initials: E
authors.lastname: Gibbs-Flournoy
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: Carson
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Shangbang
authors.initials: S
authors.lastname: Rao
authors.affiliation: Science Park - Research Division, The University of Texas MD Anderson Cancer Center, Smithville, TX, USA.
authors.forename: David L
authors.initials: DL
authors.lastname: Mitchell
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Dennis A
authors.initials: DA
authors.lastname: Simpson
authors.affiliation: Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.|Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, NC, USA.|Department of Dermatology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Thomas
authors.affiliation: Department of Biostatistics, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Joseph G
authors.initials: JG
authors.lastname: Ibrahim
authors.affiliation: Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, USA.|Curriculum in Toxicology, University of North Carolina, Chapel Hill, NC, USA.|Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.|Center for Environmental Health and Susceptibility, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: William K
authors.initials: WK
authors.lastname: Kaufmann
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D002460:Cell Line; D000071877:Checkpoint Kinase 1; D004249:DNA Damage; D004260:DNA Repair / Q000528:radiation effects; D004261:DNA Replication / Q000528:radiation effects; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism; D004171:Diploidy; D004307:Dose-Response Relationship, Radiation; D005347:Fibroblasts / Q000528:radiation effects; D006801:Humans; D008543:Melanins / Q000378:metabolism; D008544:Melanocytes / Q000166:cytology* / Q000528:radiation effects*; D008545:Melanoma / Q000473:pathology*; D010766:Phosphorylation / Q000528:radiation effects; D011494:Protein Kinases / Q000378:metabolism; D011740:Pyrimidine Dimers / Q000378:metabolism; D059807:S Phase Cell Cycle Checkpoints / Q000528:radiation effects*; D014466:Ultraviolet Rays; D000099270:Y-Family DNA Polymerases
chemical_list: D015415:Biomarkers; D000071877:Checkpoint Kinase 1; D004259:DNA-Directed DNA Polymerase; D008543:Melanins; D011494:Protein Kinases; D011740:Pyrimidine Dimers; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases
keywords: DNA replication; human; intra-S checkpoint; melanocyte; melanoma; replicon initiation; ultraviolet radiation