title: Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.
abstract: TREX2 is a 3'-DNA exonuclease specifically expressed in keratinocytes. Here, we investigated the relevance and mechanisms of TREX2 in ultraviolet (UV)-induced skin carcinogenesis. TREX2 expression was up-regulated by chronic UV exposure whereas it was de-regulated or lost in human squamous cell carcinomas (SCCs). Moreover, we identified SNPs in the TREX2 gene that were more frequent in patients with head and neck SCCs than in healthy individuals. In mice, TREX2 deficiency led to enhanced susceptibility to UVB-induced skin carcinogenesis which was preceded by aberrant DNA damage removal and degradation as well as reduced inflammation. Specifically, TREX2 loss diminished the up-regulation of IL12 and IFNγ, key cytokines related to DNA repair and antitumor immunity. In UV-treated keratinocytes, TREX2 promoted DNA repair and passage to late apoptotic stages. Notably, TREX2 was recruited to low-density nuclear chromatin and micronuclei, where it interacted with phosphorylated H2AX histone, which is a critical player in both DNA repair and cell death. Altogether, our data provide new insights in the molecular mechanisms of TREX2 activity and establish cell autonomous and non-cell autonomous functions of TREX2 in the UVB-induced skin response.
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Manils
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Diana
authors.initials: D
authors.lastname: Gómez
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Mercè
authors.initials: M
authors.lastname: Salla-Martret
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Fischer
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Fye
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Elena
authors.initials: E
authors.lastname: Marzo
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Marruecos
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Inma
authors.initials: I
authors.lastname: Serrano
authors.affiliation: Dermatology Departament, Hospital del Mar, Barcelona, Spain.
authors.forename: Rocío
authors.initials: R
authors.lastname: Salgado
authors.affiliation: Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Juan P
authors.initials: JP
authors.lastname: Rodrigo
authors.affiliation: Department of Otolaryngology, Hospital Universitario Central de Asturias, Instituto Universitario de Oncología del Principado de Asturias (IUOPA), Universidad de Oviedo, Oviedo, Spain.
authors.forename: Juana M
authors.initials: JM
authors.lastname: Garcia-Pedrero
authors.affiliation: Plataforma de Recerca Aplicada en Animal de Laboratori, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Anna M
authors.initials: AM
authors.lastname: Serafin
authors.affiliation: Plataforma de Recerca Aplicada en Animal de Laboratori, Parc Científic de Barcelona, Barcelona, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Cañas
authors.affiliation: Protecció Radiològica, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Carmen
authors.initials: C
authors.lastname: Benito
authors.affiliation: Dermatology Departament, Hospital del Mar, Barcelona, Spain.
authors.forename: Agustí
authors.initials: A
authors.lastname: Toll
authors.affiliation: Institute of Predictive and Personalized Medicine of Cancer, Badalona, Barcelona, Spain.
authors.forename: Sònia-Vanina
authors.initials: SV
authors.lastname: Forcales
authors.affiliation: Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
authors.forename: Fred W
authors.initials: FW
authors.lastname: Perrino
authors.affiliation: Research Division of Biology and Pathobiology of the Skin, Department of Dermatology, Medical University of Vienna, Vienna, Austria.
authors.forename: Leopold
authors.initials: L
authors.lastname: Eckhart
authors.affiliation: Departament de Patologia i Terapèutica Experimental, Facultat de Medicina, Campus de Bellvitge, Universitat de Barcelona, L'Hospitalet de Llobregat, Barcelona, Spain.
authors.forename: Concepció
authors.initials: C
authors.lastname: Soler
mesh_terms: D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D004249:DNA Damage; D005090:Exodeoxyribonucleases / Q000235:genetics / Q000378:metabolism*; D005260:Female; D006801:Humans; D015603:Keratinocytes / Q000201:enzymology / Q000528:radiation effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010750:Phosphoproteins / Q000235:genetics / Q000378:metabolism*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: D010750:Phosphoproteins; D005090:Exodeoxyribonucleases; C486104:TREX2 protein, human
keywords: DNA damage; TREX2; UV radiation; inflammation; skin carcinogenesis