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

• DOI: 10.1016/j.celrep.2019.01.013
• Publication Date: 2019-01-30T04:58:29Z
• Authors: 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 Guigna...; Julie Sollier; Nils P. Nickel; Mark Kaschwich; Karlene A. Cimprich; Marlene Rabinovitch
• Keywords: 0301 basic medicine; DNA Repair; QH301-705.5; Ubiquitin-Protein Ligases; Ubiquitination; Endothelial Cells; Ataxia Telangiectasia Mutated Proteins; Pulmonary Artery; Models, Biological; Genomic Instability; PPAR gamma; 03 medical and health sciences; HEK293 Cells; Homeostasis; Humans; Biology (General); DNA Damage; Protein Binding; Signal Transduction; Transcription Factors

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.