Pol II Degradation Activates Cell Death Independently from the Loss of Transcription

Overview

Journal bioRxiv

Date 2024 Dec 23

PMID 39713309

Authors

Nicholas W Harper

Gavin A Birdsall

Megan E Honeywell

Athma A Pai

Michael J Lee

Affiliations

Soon will be listed here.

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 ol II egradation-dependent poptotic esponse (). 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.

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