Pol II degradation activates cell death independently from the loss of transcription
Harper, N. W.; Birdsall, G. A.; Honeywell, M. E.; Pai, A. A.; Lee, M. J.
Show abstract
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 dysregulated gene expression. Instead, death occurs in response to the loss of Pol II protein itself, specifically loss of the enzymatic subunit, Rbp1. Loss of Pol II exclusively activates apoptosis, and expression of a transcriptionally inactive version of Rpb1 rescues cell viability. Using functional genomics, we identify a previously uncharacterized mechanism that regulates lethality following loss of Pol II, 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 signaling response that contributes to the efficacy of a wide array of anti-cancer therapies.
Matching journals
The top 4 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- CDK12 controls transcription at damaged genes and prevents MYC-induced transcription-replication conflicts 98%
- SMARCA4 deficient tumours are vulnerable to KDM6A/UTX and KDM6B/JMJD3 blockade 98%
- ANP32E drives vulnerability to ATR inhibitors by inducing R-loops-dependent Transcription Replication Conflicts in Triple Negative Breast Cancer 98%
Similar papers in this journal
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.