title: Epidermal Nbn deletion causes premature hair loss and a phenotype resembling psoriasiform dermatitis.
abstract: Nijmegen Breakage Syndrome is a disease caused by NBN mutations. Here, we report a novel function of Nbn in skin homeostasis. We found that Nbn deficiency in hair follicle (HF) progenitors promoted increased DNA damage signaling, stimulating p16Ink4a up-regulation, Trp53 stabilization and cytokines secretion leading to HF-growth arrest and hair loss. At later stages, the basal keratinocytes layer exhibited also enhanced DNA damage response but in contrast to the one in HF progenitor was not associated with pro-inflammatory cytokines expression, but rather increased proliferation, lack of differentiation and immune response resembling psoriasiform dermatitis. Simultaneous Nbn and Trp53 inactivation significantly exacerbated this phenotype, due to the lack of inhibition of pro-inflammatory cytokines secretion by Trp53. Altogether, we demonstrated novel functions of Nbn in HF maintenance and prevention of skin inflammation and we provide a mechanistic explanation that links cell intrinsic DNA maintenance with large scale morphological tissue alterations.
authors.affiliation: Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Medical School (HUMS), Heidelberg, Germany.|German Cancer Consortium (DKTK) and Heidelberg Institute of Radiation Oncology (HIRO), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Seidel
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Remus
authors.affiliation: Helmholtz Young Investigator Group Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Delacher
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Paulius
authors.initials: P
authors.lastname: Grigaravicius
authors.affiliation: Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
authors.forename: David E
authors.initials: DE
authors.lastname: Reuss
authors.affiliation: Leibniz Institute for Age Research - Fritz Lipmann Institute (FLI), Jena, Germany.
authors.forename: Lucien
authors.initials: L
authors.lastname: Frappart
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Neuropathology, Institute of Pathology, Ruprecht-Karls-Universität Heidelberg, Heidelberg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.affiliation: Helmholtz Young Investigator Group Immune Tolerance, Tumor Immunology Program, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Feuerer
authors.affiliation: Molecular and Translational Radiation Oncology, National Center for Tumor Diseases (NCT), Heidelberg University Medical School (HUMS), Heidelberg, Germany.|German Cancer Consortium (DKTK) and Heidelberg Institute of Radiation Oncology (HIRO), German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Amir
authors.initials: A
authors.lastname: Abdollahi
authors.affiliation: Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Frappart
mesh_terms: D000505:Alopecia / Q000209:etiology* / Q000473:pathology; D000818:Animals; D018797:Cell Cycle Proteins / Q000502:physiology*; D004268:DNA-Binding Proteins; D003872:Dermatitis / Q000378:metabolism / Q000473:pathology*; D004817:Epidermis / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D009687:Nuclear Proteins / Q000502:physiology*; D010641:Phenotype; D011565:Psoriasis / Q000378:metabolism / Q000473:pathology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C466108:Nijmegen breakage syndrome 1 protein, mouse; D009687:Nuclear Proteins; D016159:Tumor Suppressor Protein p53
keywords: Gerotarget; Nbn; inflammation; psoriasiform dermatitis; skin