Prmt1-mediated translation regulation is a crucial vulnerability of cancer. Mus musculus

Through an shRNA screen we have identified Prmt1 as a genetic vulnerability of p53/Rb-null murine osteosarcoma cells. Depletion of Prmt1 in p53-deficient cells impairs tumor initiation and maintenance in vitro and in vivo. Mechanistic studies reveal that translation-associated pathways are enriched for Prmt1 downstream targets, implicating a role of Prmt1 in translation control. In particular, we have shown that loss of Prmt1 leads to a the decrease in arginine methylation of the translation initiation complex, thereby disrupting its assembly and inhibiting translation. We also observed that p53/Rb-null cells are sensitive to p53-induced translation stress. Analysis of the human tumor cell Achilles data set further reveals that Prmt1 and translation-associated pathways converge on the same functional networks. We propose that targeted therapy directed to inhibition of Prmt1 and its associated translation-related pathways represents a novel and promising therapeutic strategy for p53-deficient cancer cells that exhibit dependencies on translation stress response. Overall design: RNAs were extracted from Prmt1 control and conditional knockout murine osteosarcoma cell line. In each group, RNAs from cytoplasmic, light (3 ribosomes) polysome fractions (termed Heavy), as well as total cytoplasmic RNA (termed Total) were pooled and precipitated using Trizol-LS (Thermo Scientific). 500 ug of RNAs were used to prepare cDNA libraries using the illumina Truseq v2 kit. The libraries were quantified and sequenced using Illumina Nextseq sequencer.