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

Cell Reports (Jan 2019)

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

Journal volume & issue: Vol. 26, no. 5
pp. 1333 – 1343.e7

Abstract

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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

Published in Cell Reports

ISSN: 2211-1247 (Online)
Publisher: Elsevier
Country of publisher: Netherlands
LCC subjects: Science: Biology (General)
Website: http://www.cell.com/cell-reports/home

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