Pol II degradation activates cell death independently from the loss of transcription [CRISPR_screen]

Pol II-mediated transcription is essential for eukaryotic life. While loss of transcription is thought to be universally lethal, the associated mechanisms promoting cell death are not yet known. Here, we show that death following loss of Pol II is not caused by loss of gene expression. Instead, death occurs in response to the loss of Pol II protein itself. Loss of Pol II protein exclusively activates apoptosis, and using functional genomics, we identified a previously uncharacterized pathway, which we call the Pol II Degradation-dependent Apoptotic Response (PDAR). Using the genetic dependencies of PDAR, we identify clinically used drugs that owe their efficacy to a PDAR-dependent mechanism. Our findings unveil a novel apoptotic pathway that contributes to the efficacy of a wide array of anti-cancer therapies. Genome-wide CRISPR KO screen of U2OS-Cas9 cells treated with or without 1 µM triptolide for 32 hours. T0 samples were taken immediately prior to drugging. Drug treated cells were then mechanically separated into live and dead fractions.