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

Using proteomic approaches, we uncovered a DNA damage response (DDR) function for peroxisome proliferator activated receptor gamma (PPAR gamma) through its interaction with the DNA damage sensor MRE11-RAD50-NBS1 (MRN) and the E3 ubiquitin ligase UBR5. We show that PPAR gamma promotes ATM signaling and is essential for UBR5 activity targeting ATM interactor (ATMIN). PPAR gamma 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 PPAR gamma DDR functions by using pulmonary arterial hypertension (PAH) as a model that has impaired PPAR gamma signaling related to endothelial cell (EC) dysfunction and unresolved DNA damage. In pulmonary arterial ECs (PAECs) from PAH patients, we observed disrupted PPAR gamma-UBR5 interaction, heightened ATMIN expression, and DNA lesions. Blocking ATMIN in PAH PAEC restores ATM activation. Thus, impaired PPAR gamma DDR functions may explain the genomic instability and loss of endothelial homeostasis in PAH.