Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.

Manils, Joan; Gómez, Diana; Salla-Martret, Mercè; Fischer, Heinz; Fye, Jason M.; Marzo, Elena; Marruecos, Laura; Serrano, Inma; Salgado, Rocío; Rodrigo, Juan P.; Garcia-Pedrero, Juana M.; Serafin, Anna M.; Cañas, Xavier; Benito, María del Carmen; Toll Abelló, Agustín; Forcales Fernàndez, Sonia-Vanina; Perrino, Fred W.; Eckhart, Leopold; Soler Prat, Concepció

Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.

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dc.contributor.author Manils, Joanca
dc.contributor.author Gómez, Dianaca
dc.contributor.author Salla-Martret, Mercèca
dc.contributor.author Fischer, Heinzca
dc.contributor.author Fye, Jason M.ca
dc.contributor.author Marzo, Elenaca
dc.contributor.author Marruecos, Lauraca
dc.contributor.author Serrano, Inmaca
dc.contributor.author Salgado, Rocíoca
dc.contributor.author Rodrigo, Juan P.ca
dc.contributor.author Garcia-Pedrero, Juana M.ca
dc.contributor.author Serafin, Anna M.ca
dc.contributor.author Cañas, Xavierca
dc.contributor.author Benito, María del Carmenca
dc.contributor.author Toll Abelló, Agustínca
dc.contributor.author Forcales Fernàndez, Sonia-Vaninaca
dc.contributor.author Perrino, Fred W.ca
dc.contributor.author Eckhart, Leopoldca
dc.contributor.author Soler Prat, Concepcióca
dc.date.accessioned 2015-11-18T08:22:45Z
dc.date.available 2015-11-18T08:22:45Z
dc.date.issued 2015
dc.description.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.ca
dc.description.sponsorship This study was supported by the Ministerio de Ciencia e Innovación grants BFU2009-07501 and BFU2010- 15674 (CS), and the NIH grant GM069962 (FWP). Joan Manils and Diana Gómez are recipients of predoctoral fellowships, respectively, from the Ministerio de Economía y Competitividad and the Universitat de Barcelona.
dc.format.mimetype application/pdfca
dc.identifier.citation Manils J, Gómez D, Salla-Martret M, Fischer H, Fye JM, Marzo E. et al. Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis. Oncotarget. 2015 Sep 8;6(26):22375-96. DOI: 10.18632/oncotarget.4296ca
dc.identifier.doi http://dx.doi.org/10.18632/oncotarget.4296
dc.identifier.issn 1949-2553
dc.identifier.uri http://hdl.handle.net/10230/25128
dc.language.iso engca
dc.publisher Impact Journalsca
dc.relation.ispartof Oncotarget. 2015 Sep 8;6(26):22375-96
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2009-07501
dc.relation.projectID info:eu-repo/grantAgreement/ES/3PN/BFU2010- 15674
dc.rights.accessRights info:eu-repo/semantics/openAccessca
dc.rights.uri http://creativecommons.org/licenses/by/3.0/ca
dc.subject.keyword DNA damage
dc.subject.keyword TREX2
dc.subject.keyword UV radiation
dc.subject.keyword Inflammation
dc.subject.keyword Skin carcinogenesis
dc.title Multifaceted role of TREX2 in the skin defense against UV-induced skin carcinogenesis.ca
dc.type info:eu-repo/semantics/articleca
dc.type.version info:eu-repo/semantics/publishedVersionca

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