A bicyclic monoterpene diol and UVB stimulate BRCA1 phosphorylation in human keratinocytes.
BRCA1 (breast cancer-associated gene 1) is a tumor suppressor gene that plays a role in DNA repair when phosphorylated. Many DNA-damaging agents including UVC and hydrogen peroxide have been shown to induce phosphorylation of BRCA1. Results of this study now show that both UVB and a bicyclic monoterpene diol (BMT diol) result in phosphorylation of BRCA1. This phosphorylation was maximal 2 h after treatment with either agent and declined to basal levels by 24 h. Inhibitor studies revealed that both UVB and the BMT diol phosphorylate BRCA1 through the FK506-binding protein-FKBP rapamycin-associated binding protein pathway, but the BMT diol also led to phosphorylation of BRCA1 through casein kinase II. This suggests that the signaling pathways for UVB and the BMT diol may diverge. Results of this study also show that the BMT diol stimulates the repair of UVB-induced cyclobutane pyrimidine dimers (CPD). Inhibitors of BMT diol-induced BRCA1 phosphorylation blocked the BMT diol-stimulated repair of CPD. This indicates that the BMT diol induces the phosphorylation of BRCA1, which, in turn, leads to an increase in repair of UVB-induced CPD. Therefore, this BMT diol may be useful for ameliorating the damaging effects of UVB.
Canning
Matthew T
MT
AGI Dermatics, Freeport, NY 11520, USA. mcanning@agiderm.com
Brown
David A
DA
Yarosh
Daniel B
DB
D019313:BRCA1 Protein / Q000378:metabolism*; D002460:Cell Line; D004260:DNA Repair / Q000187:drug effects; D004004:Dichlororibofuranosylbenzimidazole / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects* / Q000378:metabolism / Q000528:radiation effects*; D039821:Monoterpenes / Q000494:pharmacology*; D009636:Norbornanes / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology; D010766:Phosphorylation / Q000187:drug effects / Q000528:radiation effects; D011740:Pyrimidine Dimers / Q000528:radiation effects; D011810:Quinoxalines / Q000494:pharmacology; D020123:Sirolimus / Q000494:pharmacology; D013997:Time Factors; D014466:Ultraviolet Rays
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; C480566:2,2-dimethyl-3-propanyldiol-norbornane; D019313:BRCA1 Protein; D039821:Monoterpenes; D009636:Norbornanes; D010069:Oxadiazoles; D011740:Pyrimidine Dimers; D011810:Quinoxalines; D004004:Dichlororibofuranosylbenzimidazole; D020123:Sirolimus