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Publication

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

Cell reports | 2019

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.

Pubmed ID: 30699358 RIS Download

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Associated grants

Agency: NHLBI NIH HHS, United States
Id: R01 HL087118
Agency: NHLBI NIH HHS, United States
Id: R24 HL123767
Agency: NCATS NIH HHS, United States
Id: UL1 TR002240
Agency: NCRR NIH HHS, United States
Id: UL1 RR024986
Agency: NCRR NIH HHS, United States
Id: S10 RR027425
Agency: NHLBI NIH HHS, United States
Id: K12 HL120001
Agency: NCI NIH HHS, United States
Id: P30 CA124435
Agency: NHLBI NIH HHS, United States
Id: R01 HL122887

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