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RINT1 is essential to pancreas ductal adenocarcinoma (PDAC) homeostasis
13 August 2018 (online)
RINT1 (RAD50-interacting protein 1) is a multifunctional protein playing a role in cell cycle regulation, genomic stability, telomere maintenance, ER-Golgi trafficking and autophagy. Here, we show that RINT1-depletion in PDAC cell lines leads to severe growth defects associated with massive Golgi fragmentation and G2/M cell cycle arrest leading to genomic instability. These data suggest that RINT1 homeostasis is essential for PDAC survival and represents therefore a putative therapeutic target. To characterize more in details the mechanisms of RINT1 regulation and to ultimately identify RINT1-dependent pathways that could be targeted in PDAC, we performed an extensive interaction study through yeast-two hybrid assay and mass spectrometry. We discovered hundreds of new RINT1-interaction partners including proteins involved in mitotic events supporting our preliminary data indicating an increase in genomic instability in PDAC cell lines. Moreover, we identified E3 ligases interacting with RINT1 allowing a better understanding of RINT1 biological function. In addition, we identify several post-translational modifications including ubiquitination and sumoylation and demonstrated that ubiquitination is a key regulator of RINT1 stability and biological function. Altogether, these data reveal the key role of RINT1 in PDAC homeostasis and identify multiple RINT1-post-translational modifications and protein-protein interaction partners that could be targeted in novel therapeutic approaches.