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PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis.
Li, Caiyun G; Mahon, Cathal; Sweeney, Nathaly M; Verschueren, Erik; Kantamani, Vivek; Li, Dan; Hennigs, Jan K; Marciano, David P; Diebold, Isabel; Abu-Halawa, Ossama; Elliott, Matthew; Sa, Silin; Guo, Feng; Wang, Lingli; Cao, Aiqin; Guignabert, Christophe; Sollier, Julie; Nickel, Nils P; Kaschwich, Mark; Cimprich, Karlene A; Rabinovitch, Marlene.
Afiliación
  • Li CG; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Mahon C; California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USA; Department of Pharmaceutical Chemistry, University of California-San Francisco, San Francisco, CA 94158, USA.
  • Sweeney NM; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Verschueren E; California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USA.
  • Kantamani V; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Li D; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Hennigs JK; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Marciano DP; Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Diebold I; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Abu-Halawa O; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Elliott M; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Sa S; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Guo F; Department of Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Wang L; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Cao A; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Guignabert C; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Sollier J; Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Nickel NP; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Kaschwich M; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Cimprich KA; Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USA.
  • Rabinovitch M; The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA. Electronic address: marlener@stanford.edu.
Cell Rep ; 26(5): 1333-1343.e7, 2019 01 29.
Article en En | MEDLINE | ID: mdl-30699358
Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor γ (PPARγ) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPARγ promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPARγ depletion increases ATMIN protein independent of transcription and suppresses DDR-induced ATM signaling. Blocking ATMIN in this context restores ATM activation and DNA repair. We illustrate the physiological relevance of PPARγ DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPARγ signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPARγ-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPARγ DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH.
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Endoteliales / Ubiquitina-Proteína Ligasas / PPAR gamma / Reparación del ADN / Homeostasis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos
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Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Asunto principal: Factores de Transcripción / Células Endoteliales / Ubiquitina-Proteína Ligasas / PPAR gamma / Reparación del ADN / Homeostasis Tipo de estudio: Prognostic_studies Límite: Humans Idioma: En Revista: Cell Rep Año: 2019 Tipo del documento: Article País de afiliación: Estados Unidos