title: Cyclosporin A inhibits nucleotide excision repair via downregulation of the xeroderma pigmentosum group A and G proteins, which is mediated by calcineurin inhibition.
abstract: Cyclosporin A (CsA) inhibits nucleotide excision repair (NER) in human cells, a process that contributes to the skin cancer proneness in organ transplant patients. We investigated the mechanisms of CsA-induced NER reduction by assessing all xeroderma pigmentosum (XP) genes (XPA-XPG). Western blot analyses revealed that XPA and XPG protein expression was reduced in normal human GM00637 fibroblasts exposed to 0.1 and 0.5 μm CsA. Interestingly, the CsA treatment reduced XPG, but not XPA, mRNA expression. Calcineurin knockdown in GM00637 fibroblasts using RNAi led to similar results suggesting that calcineurin-dependent signalling is involved in XPA and XPG protein regulation. CsA-induced reduction in NER could be complemented by the overexpression of either XPA or XPG protein. Likewise, XPA-deficient fibroblasts with stable overexpression of XPA (XP2OS-pCAH19WS) did not show the inhibitory effect of CsA on NER. In contrast, XPC-deficient fibroblasts overexpressing XPC showed CsA-reduced NER. Our data indicate that the CsA-induced inhibition of NER is a result of downregulation of XPA and XPG protein in a calcineurin-dependent manner.
authors.affiliation: Department of Dermatology, Venerology, and Allergology, Georg-August-University, Goettingen, Goettingen, Germany.
authors.forename: Christiane
authors.initials: C
authors.lastname: Kuschal
authors.forename: Kai-Martin
authors.initials: KM
authors.lastname: Thoms
authors.forename: Lars
authors.initials: L
authors.lastname: Boeckmann
authors.forename: Petra
authors.initials: P
authors.lastname: Laspe
authors.forename: Antje
authors.initials: A
authors.lastname: Apel
authors.forename: Michael P
authors.initials: MP
authors.lastname: Schön
authors.forename: Steffen
authors.initials: S
authors.lastname: Emmert
mesh_terms: D019703:Calcineurin / Q000235:genetics; D065095:Calcineurin Inhibitors; D002460:Cell Line; D016572:Cyclosporine / Q000009:adverse effects*; D004260:DNA Repair / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D015536:Down-Regulation / Q000187:drug effects; D004720:Endonucleases / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007166:Immunosuppressive Agents / Q000009:adverse effects; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000209:etiology; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D019737:Transplants / Q000009:adverse effects; D014983:Xeroderma Pigmentosum / Q000150:complications / Q000235:genetics / Q000378:metabolism; D051760:Xeroderma Pigmentosum Group A Protein / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000099250:DNA Excision Repair Protein ERCC-5
chemical_list: D019703:Calcineurin; D065095:Calcineurin Inhibitors; D016572:Cyclosporine; D004268:DNA-Binding Proteins; D004720:Endonucleases; D007166:Immunosuppressive Agents; D009687:Nuclear Proteins; D012333:RNA, Messenger; D014157:Transcription Factors; D051760:Xeroderma Pigmentosum Group A Protein; D000099250:DNA Excision Repair Protein ERCC-5; C497314:XPA protein, human; C086984:XPC protein, human