The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes

Douglas E. Brash, N. Wikonkál, E. Remenyik, Gijsbertus T J Van der Horst, Errol C. Friedberg, David L. Cheo, Harry Van Steeg, Anja Westerman, Henk J. Van Kranen

Research output: Contribution to journalArticle

37 Citations (Scopus)

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 ≈ 89% of the Mdm2 response.

Original languageEnglish
Pages (from-to)1234-1240
Number of pages7
JournalJournal of Investigative Dermatology
Volume117
Issue number5
DOIs
Publication statusPublished - 2001

Fingerprint

Sunburn
DNA Damage
Genes
DNA
Apoptosis
Keratinocytes
Repair
DNA Repair
Genome
Tumor Suppressor Proteins
Cornea
Nucleotides
Degradation

Keywords

  • Apoptosis
  • Cockayne syndrome
  • Mdm2 protein
  • MeSH
  • Protein p53
  • Ultraviolet rays
  • Xeroderma pigmentosum

ASJC Scopus subject areas

  • Dermatology

Cite this

The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes. / Brash, Douglas E.; Wikonkál, N.; Remenyik, E.; Van der Horst, Gijsbertus T J; Friedberg, Errol C.; Cheo, David L.; Van Steeg, Harry; Westerman, Anja; Van Kranen, Henk J.

In: Journal of Investigative Dermatology, Vol. 117, No. 5, 2001, p. 1234-1240.

Research output: Contribution to journalArticle

Brash, Douglas E. ; Wikonkál, N. ; Remenyik, E. ; Van der Horst, Gijsbertus T J ; Friedberg, Errol C. ; Cheo, David L. ; Van Steeg, Harry ; Westerman, Anja ; Van Kranen, Henk J. / The DNA damage signal for Mdm2 regulation, Trp53 induction, and sunburn cell formation in vivo originates from actively transcribed genes. In: Journal of Investigative Dermatology. 2001 ; Vol. 117, No. 5. pp. 1234-1240.
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AU - Wikonkál, N.

AU - Remenyik, E.

AU - Van der Horst, Gijsbertus T J

AU - Friedberg, Errol C.

AU - Cheo, David L.

AU - Van Steeg, Harry

AU - Westerman, Anja

AU - Van Kranen, Henk J.

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AB - 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 ≈ 89% of the Mdm2 response.

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