title: The loss of ATP2C1 impairs the DNA damage response and induces altered skin homeostasis: Consequences for epidermal biology in Hailey-Hailey disease.
abstract: Mutation of the Golgi Ca(2+)-ATPase ATP2C1 is associated with deregulated calcium homeostasis and altered skin function. ATP2C1 mutations have been identified as having a causative role in Hailey-Hailey disease, an autosomal-dominant skin disorder. Here, we identified ATP2C1 as a crucial regulator of epidermal homeostasis through the regulation of oxidative stress. Upon ATP2C1 inactivation, oxidative stress and Notch1 activation were increased in cultured human keratinocytes. Using RNA-seq experiments, we found that the DNA damage response (DDR) was consistently down-regulated in keratinocytes derived from the lesions of patients with Hailey-Hailey disease. Although oxidative stress activates the DDR, ATP2C1 inactivation down-regulates DDR gene expression. We showed that the DDR response was a major target of oxidative stress-induced Notch1 activation. Here, we show that this activation is functionally important because early Notch1 activation in keratinocytes induces keratinocyte differentiation and represses the DDR. These results indicate that an ATP2C1/NOTCH1 axis might be critical for keratinocyte function and cutaneous homeostasis, suggesting a plausible model for the pathological features of Hailey-Hailey disease.
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Samantha
authors.initials: S
authors.lastname: Cialfi
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Loredana
authors.initials: L
authors.lastname: Le Pera
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: De Blasio
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Germano
authors.initials: G
authors.lastname: Mariano
authors.affiliation: Center for Life Nano Science@Sapienza, Istituto Italiano di Tecnologia, Rome, Italy.
authors.forename: Rocco
authors.initials: R
authors.lastname: Palermo
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Azzurra
authors.initials: A
authors.lastname: Zonfrilli
authors.affiliation: Department of Biology and Biotechnology "C. Darwin"; Sapienza University of Rome, Rome, Italy.
authors.forename: Daniela
authors.initials: D
authors.lastname: Uccelletti
authors.affiliation: Department of Biology and Biotechnology "C. Darwin"; Sapienza University of Rome, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Palleschi
authors.affiliation: Porphyria Center, San Gallicano Institute IRCCS, Rome, Italy.
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Biolcati
authors.affiliation: Porphyria Center, San Gallicano Institute IRCCS, Rome, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Barbieri
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.|Istituto Pasteur Italia, Fondazione Cenci-Bolognetti, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Screpanti
authors.affiliation: Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.
authors.forename: Claudio
authors.initials: C
authors.lastname: Talora
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism; D000252:Calcium-Transporting ATPases / Q000235:genetics*; D002454:Cell Differentiation; D004249:DNA Damage; D004817:Epidermis / Q000378:metabolism* / Q000473:pathology; D015870:Gene Expression; D006706:Homeostasis; D006801:Humans; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D018384:Oxidative Stress; D016506:Pemphigus, Benign Familial / Q000235:genetics / Q000473:pathology*; D051881:Receptor, Notch1 / Q000378:metabolism*
chemical_list: D051881:Receptor, Notch1; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C403624:ATP2C1 protein, human; D000252:Calcium-Transporting ATPases