PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis
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
Affiliations
Caiyun G. Li
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Cathal Mahon
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
Nathaly M. Sweeney
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Erik Verschueren
California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USA
Vivek Kantamani
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Dan Li
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Jan K. Hennigs
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
David P. Marciano
Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA
Isabel Diebold
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Ossama Abu-Halawa
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Matthew Elliott
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Silin Sa
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Feng Guo
Department of Medicine, Stanford School of Medicine, Stanford, CA 94305, USA
Lingli Wang
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Aiqin Cao
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Christophe Guignabert
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Julie Sollier
Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USA
Nils P. Nickel
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Mark Kaschwich
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA
Karlene A. Cimprich
Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USA
Marlene Rabinovitch
The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA; Corresponding author
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
