PRMT1-dependent Arginine methylation regulates replication stress response through DNA-protein kinase

PRMT1 is the major Arginine methyltransferase in mammalian cells and its over-expression in human cancer has been linked to poor response to cancer therapy. Here, combining mass spectrometry-based global methyl-proteomics with genome-wide mRNA expression profiling, we identify PRMT1 and its associated Arginine methylation as a regulatory hubs controlling cancer cell response to replicative stress agents. We show that DNA-PK binds to PRMT1 and regulates both its subcellular localization and activity, leading to PRMT1 recruitment to drug-stalled replication forks and channelling its methyl-transferase activity from its soluble targets towards Arginine 3 of histone H4. This DNA-PK-PRMT1 axis is required for the induction of the Senescence-Associated Secretory Phenotype, which sustains cell cycle arrest and protects cells from apoptosis. Our data show that Arginine-methylation regulates the adaptive response of cancer cell to replicative stress agents and might be targeted to sensitize cancer cells to genotoxic chemotherapeutics 8 samples of SK-OV-3 ovarian cancer cells differentially treated were analyzed; two biological replicates were performed for each sample. "Emp" indicates shScramble cells that is the control used as a reference. "C20"indicates cell treatment with cisplatin (20 micromolar for 24 hours), whereas B6, B8 and B10 represent three different shRNA sequences used to knock down PRMT1 expression.