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

doi:10.1016/j.celrep.2019.01.013

PPARγ Interaction with UBR5/ATMIN Promotes DNA Repair to Maintain Endothelial Homeostasis

Cell Rep. 2019 Jan 29;26(5):1333-1343.e7. doi: 10.1016/j.celrep.2019.01.013.

Authors

Caiyun G Li¹, Cathal Mahon², Nathaly M Sweeney¹, Erik Verschueren³, Vivek Kantamani¹, Dan Li¹, Jan K Hennigs¹, David P Marciano⁴, Isabel Diebold¹, Ossama Abu-Halawa¹, Matthew Elliott¹, Silin Sa¹, Feng Guo⁵, Lingli Wang¹, Aiqin Cao¹, Christophe Guignabert¹, Julie Sollier⁶, Nils P Nickel¹, Mark Kaschwich¹, Karlene A Cimprich⁶, Marlene Rabinovitch⁷

Affiliations

¹ The Vera Moulton Wall Center for Pulmonary Vascular Disease, Department of Pediatrics and Cardiovascular Institute, Stanford School of Medicine, Stanford, CA 94305, USA.
² 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.
³ California Institute for Quantitative Biosciences, Department of Cellular and Molecular Pharmacology, University of California-San Francisco, San Francisco, CA 94158, USA.
⁴ Department of Genetics, Stanford School of Medicine, Stanford, CA 94305, USA.
⁵ Department of Medicine, Stanford School of Medicine, Stanford, CA 94305, USA.
⁶ Department of Chemical and Systems Biology, Stanford School of Medicine, Stanford, CA 94305, USA.
⁷ 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.

Abstract

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.

Keywords: ATM; DNA damage; MRN; PPARγ; endothelial cells; pulmonary hypertension; vascular biology.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Ataxia Telangiectasia Mutated Proteins / metabolism
DNA Damage
DNA Repair*
Endothelial Cells / metabolism*
Genomic Instability
HEK293 Cells
Homeostasis*
Humans
Models, Biological
PPAR gamma / metabolism*
Protein Binding
Pulmonary Artery / pathology
Signal Transduction
Transcription Factors / metabolism*
Ubiquitin-Protein Ligases / metabolism*
Ubiquitination

Substances

ATMIN protein, human
PPAR gamma
Transcription Factors
UBR5 protein, human
Ubiquitin-Protein Ligases
Ataxia Telangiectasia Mutated Proteins

Abstract

Publication types

MeSH terms

Substances

Grants and funding