PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis
Summary: 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...
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| Format: | Article |
| Language: | English |
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Elsevier
2019-01-01
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| Series: | Cell Reports |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S221112471930021X |
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doaj-4b2b333c73b8412195c17cfba09e970c |
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Caiyun G. Li Cathal Mahon Nathaly M. Sweeney Erik Verschueren Vivek Kantamani Dan Li Jan K. Hennigs David P. Marciano Isabel Diebold Ossama Abu-Halawa Matthew Elliott Silin Sa Feng Guo Lingli Wang Aiqin Cao Christophe Guignabert Julie Sollier Nils P. Nickel Mark Kaschwich Karlene A. Cimprich Marlene Rabinovitch |
| spellingShingle |
Caiyun G. Li Cathal Mahon Nathaly M. Sweeney Erik Verschueren Vivek Kantamani Dan Li Jan K. Hennigs David P. Marciano Isabel Diebold Ossama Abu-Halawa Matthew Elliott Silin Sa Feng Guo Lingli Wang Aiqin Cao Christophe Guignabert Julie Sollier Nils P. Nickel Mark Kaschwich Karlene A. Cimprich Marlene Rabinovitch PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis Cell Reports |
| author_facet |
Caiyun G. Li Cathal Mahon Nathaly M. Sweeney Erik Verschueren Vivek Kantamani Dan Li Jan K. Hennigs David P. Marciano Isabel Diebold Ossama Abu-Halawa Matthew Elliott Silin Sa Feng Guo Lingli Wang Aiqin Cao Christophe Guignabert Julie Sollier Nils P. Nickel Mark Kaschwich Karlene A. Cimprich Marlene Rabinovitch |
| author_sort |
Caiyun G. Li |
| title |
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis |
| title_short |
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis |
| title_full |
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis |
| title_fullStr |
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis |
| title_full_unstemmed |
PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis |
| title_sort |
pparγ interaction with ubr5/atmin promotes dna repair to maintain endothelial homeostasis |
| publisher |
Elsevier |
| series |
Cell Reports |
| issn |
2211-1247 |
| publishDate |
2019-01-01 |
| description |
Summary: 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. : Li et al. identify PPARγ interactions with MRN and UBR5. PPARγ promotes UBR5-mediated ATMIN degradation, necessary for ATM activation upon DNA damage. Pulmonary arterial hypertension (PAH) endothelial cells exhibit genomic instability and disrupted PPARγ-UBR5 interaction. Blocking ATMIN restores ATM signaling in these cells, highlighting the significance of the PPARγ-ATMIN axis. Keywords: PPARγ, DNA damage, vascular biology, pulmonary hypertension, endothelial cells, ATM, MRN |
| url |
http://www.sciencedirect.com/science/article/pii/S221112471930021X |
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doaj-4b2b333c73b8412195c17cfba09e970c2020-11-25T01:30:15ZengElsevierCell Reports2211-12472019-01-0126513331343.e7PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial HomeostasisCaiyun G. Li0Cathal Mahon1Nathaly M. Sweeney2Erik Verschueren3Vivek Kantamani4Dan Li5Jan K. Hennigs6David P. Marciano7Isabel Diebold8Ossama Abu-Halawa9Matthew Elliott10Silin Sa11Feng Guo12Lingli Wang13Aiqin Cao14Christophe Guignabert15Julie Sollier16Nils P. Nickel17Mark Kaschwich18Karlene A. Cimprich19Marlene Rabinovitch20The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USACalifornia 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, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USACalifornia Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USADepartment of Genetics, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USADepartment of Medicine, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USADepartment of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USADepartment of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USAThe Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Corresponding authorSummary: 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. : Li et al. identify PPARγ interactions with MRN and UBR5. PPARγ promotes UBR5-mediated ATMIN degradation, necessary for ATM activation upon DNA damage. Pulmonary arterial hypertension (PAH) endothelial cells exhibit genomic instability and disrupted PPARγ-UBR5 interaction. Blocking ATMIN restores ATM signaling in these cells, highlighting the significance of the PPARγ-ATMIN axis. Keywords: PPARγ, DNA damage, vascular biology, pulmonary hypertension, endothelial cells, ATM, MRNhttp://www.sciencedirect.com/science/article/pii/S221112471930021X |