title: The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes.
abstract: The stratum corneum and DNA repair do not completely protect keratinocytes from ultraviolet B. A third defense prevents cells with DNA photoproducts from becoming precancerous mutant cells: apoptosis of ultraviolet-damaged keratinocytes ("sunburn cells"). As signals for ultraviolet-induced apoptosis, some studies implicate DNA photoproducts in actively transcribed genes; other studies implicate non-nuclear signals. We traced and quantitated the in vivo DNA signal through several steps in the apoptosis-signaling pathway in haired mice. Homozygous inactivation of Xpa, Csb, or Xpc nucleotide excision repair genes directed the accumulation of DNA photoproducts to specific genome regions. Repair-defective Xpa-/- mice were 7-10-fold more sensitive to sunburn cell induction than wild-type mice, indicating that 86-90% of the ultraviolet B signal for keratinocyte apoptosis involved repairable photoproducts in DNA; the remainder involves unrepaired DNA lesions or nongenomic targets. Csb-/- mice, defective only in excising photoproducts from actively transcribed genes, were as sensitive as Xpa-/-, indicating that virtually all of the DNA signal originates from photoproducts in active genes. Conversely, Xpc-/- mice, defective in repairing the untranscribed majority of the genome, were as resistant to apoptosis as wild type. Sunburn cell formation requires the Trp53 tumor suppressor protein; 90-96% of the signal for its induction in vivo involved transcribed genes. Mdm2, which regulates the stability of Trp53 through degradation, was induced in vivo by low ultraviolet B doses but was suppressed at erythemal doses. DNA photoproducts in actively transcribed genes were involved in approximately 89% of the Mdm2 response.
authors.affiliation: Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, Conneticut 06520-8040, USA. douglas.brash@yale.edu
authors.forename: D E
authors.initials: DE
authors.lastname: Brash
authors.forename: N M
authors.initials: NM
authors.lastname: Wikonkal
authors.forename: E
authors.initials: E
authors.lastname: Remenyik
authors.forename: G T
authors.initials: GT
authors.lastname: van der Horst
authors.forename: E C
authors.initials: EC
authors.lastname: Friedberg
authors.forename: D L
authors.initials: DL
authors.lastname: Cheo
authors.forename: H
authors.initials: H
authors.lastname: van Steeg
authors.forename: A
authors.initials: A
authors.lastname: Westerman
authors.forename: H J
authors.initials: HJ
authors.lastname: van Kranen
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D004247:DNA / Q000528:radiation effects; D004249:DNA Damage / Q000502:physiology*; D004307:Dose-Response Relationship, Radiation; D004890:Erythema / Q000209:etiology; D016678:Genome; D051379:Mice; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors / Q000502:physiology*; D051736:Proto-Oncogene Proteins c-mdm2; D011832:Radiation Injuries / Q000150:complications; D015398:Signal Transduction / Q000502:physiology; D013471:Sunburn / Q000473:pathology*; D014158:Transcription, Genetic / Q000502:physiology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D014466:Ultraviolet Rays
chemical_list: D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D016159:Tumor Suppressor Protein p53; D004247:DNA; C497207:Mdm2 protein, mouse; D051736:Proto-Oncogene Proteins c-mdm2