Spironolactone depletes the XPB protein and inhibits DNA damage responses in UVB-irradiated human skin

UVB wavelengths of light induce the formation of photoproducts in genomic DNA that are potentially mutagenic and detrimental to epidermal cell function. Interestingly, 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 (xeroderma pigmentosum group B). Using normal human keratinocytes in vitro and skin explants ex vivo, we find 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 the ATR/ATM DNA damage kinase signaling.