Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin

Michael G. Kemp, Smita Krishnamurthy, Michael N. Kent, David L. Schumacher, Priyanka Sharma, Katherine J.D.A. Excoffon, Jeffrey Travers

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

UVB wavelengths of light induce the formation of photoproducts in genomic DNA that are potentially mutagenic and detrimental to epidermal cell function. The mineralocorticoid and androgen receptor antagonist spironolactone (SP) was recently identified as an inhibitor of UV photoproduct removal in human cancer cells in vitro via its ability to promote the rapid proteolytic degradation of the DNA repair protein XPB. Using normal human keratinocytes in vitro and skin explants ex vivo, we found that SP rapidly depleted XPB protein in both systems and abrogated two major responses to UVB-induced DNA damage, including the removal of UV photoproducts from genomic DNA and the activation of ATR/ATM DNA damage kinase signaling. These effects were also correlated with both mutagenesis and a predisposition to UVB-induced cell death but were unique to SP, because neither the SP metabolites canrenone and 7α-thiomethylspironolactone nor the more specific mineralocorticoid receptor antagonist eplerenone affected XPB protein levels or the UVB response. Our findings provide an approach for studying XPB and its roles in the UVB DNA damage response in human skin ex vivo and indicate that SP may increase UVB mutagenesis and skin cancer risk in certain individuals.

Original languageEnglish (US)
JournalJournal of Investigative Dermatology
DOIs
StateAccepted/In press - Jan 1 2018
Externally publishedYes

Fingerprint

Spironolactone
DNA Damage
Skin
DNA
Mineralocorticoid Receptor Antagonists
Mutagenesis
Proteins
Canrenone
Androgen Receptor Antagonists
Polynucleotide 5'-Hydroxyl-Kinase
Skin Neoplasms
Keratinocytes
DNA Repair
Automatic teller machines
Cell death
Metabolites
Cell Death
Repair
Phosphotransferases
Light

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Dermatology
  • Cell Biology

Cite this

Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin. / Kemp, Michael G.; Krishnamurthy, Smita; Kent, Michael N.; Schumacher, David L.; Sharma, Priyanka; Excoffon, Katherine J.D.A.; Travers, Jeffrey.

In: Journal of Investigative Dermatology, 01.01.2018.

Research output: Contribution to journalArticle

Kemp, Michael G. ; Krishnamurthy, Smita ; Kent, Michael N. ; Schumacher, David L. ; Sharma, Priyanka ; Excoffon, Katherine J.D.A. ; Travers, Jeffrey. / Spironolactone Depletes the XPB Protein and Inhibits DNA Damage Responses in UVB-Irradiated Human Skin. In: Journal of Investigative Dermatology. 2018.
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