PRMT1 Is Recruited via DNA-PK to Chromatin Where It Sustains the Senescence-Associated Secretory Phenotype in Response to Cisplatin

Summary: Protein arginine methyltransferase 1 (PRMT1) is overexpressed in various human cancers and linked to poor response to chemotherapy. Various PRMT1 inhibitors are currently under development; yet, we do not fully understand the mechanisms underpinning PRMT1 involvement in tumorigenesis and chemoresistance. Using mass spectrometry-based proteomics, we identified PRMT1 as regulator of arginine methylation in ovarian cancer cells treated with cisplatin. We showed that DNA-dependent protein kinase (DNA-PK) binds to and phosphorylates PRMT1 in response to cisplatin, inducing its chromatin recruitment and redirecting its enzymatic activity toward Arg3 of histone H4 (H4R3). On chromatin, the DNA-PK/PRMT1 axis induces senescence-associated secretory phenotype through H4R3me2a deposition at pro-inflammatory gene promoters. Finally, PRMT1 inhibition reduces the clonogenic growth of cancer cells exposed to low doses of cisplatin, sensitizing them to apoptosis. While unravelling the role of PRMT1 in response to genotoxic agents, our findings indicate the possibility of targeting PRMT1 to overcome chemoresistance in cancer. : Protein arginine methyltransferase 1 (PRMT1) overexpression is linked to cancer chemoresistance, but the mechanism is still unclear. Musiani et al. show that, upon cisplatin, PRMT1 is recruited by DNA-dependent protein kinase (DNA-PK) to chromatin, where it sustains the transcription of genes involved in the senescence-associated secretory phenotype (SASP), thus protecting cells from drug-induced apoptosis. Keywords: arginine methylation, MS-based proteomics, replication stress response, PRMT1, SASP, transcription, cisplatin, epigenetic drugs, DNA-P

Structure/Function Relationships of Phospholipases C Beta

Phospholipases C beta (PLC-βs) are essential components of the signal transduction of metazoans. They catalyze the production of the second messengers inositol-1,4,5-trisphosphate (IP3) and diacylglycerol (DAG) from the hydrolysis of phosphatidylinositol-4,5-bisphosphate (PIP2). These enzymes are activated by G-protein-coupled receptors (GPCRs) through the interaction with the alpha subunit of heterotrimeric G-proteins belonging to the Gq family (Gαq), the Gβγ subunits released by the inhibitory G-protein (Gi) and Ca2+ ions. Here we review current structural insights on these important proteins, with a particular focus on the most structurally characterized isoform (PLC-β3) and the activation mechanism operated by Gαq. We propose, following the lead of recent studies, that a tight combination of experiments and molecular simulations are instrumental in further enlightening the structure/function understanding of PLC-βs. - See more at: http://www.eurekaselect.com/116059/article#sthash.cojH1BB1.dpu