Congrats to Nick Harper and the rest of the team!
7/end 🧪

A 3rd surprise: PDAR accounts for the activity of many cancer drugs, including several that have never been considered transcriptional inhibitors.

Drugs that cause bulky DNA lesions activate many stress pathways… but activating PDAR accounts for their ability to kill cancer cells.
6/n 🧪

The 2nd surprise is related to how PDAR works: cells sense the loss of the hypo-phosphorylated (i.e., not actively transcribing) forms of RNA Pol II.

Yes, this is about loss of gene expression, but it doesn’t really have anything to do with loss of transcriptional activity or loss of RNA 😳
5/n 🧪

With activation of PDAR, cells die proactively. This occurs before cells really experience any stress from the dysregulated gene expression, and the outcome isn’t left to chance.
4/n 🧪

The 1st surprise is simply that PDAR exists.

Intuitively, complete loss of gene expression should be sufficient to kill a cell… and that is true, but it takes a LOOONG time and cells die using an array of different mechanisms (e.g., inflammatory/necrotic, apoptotic, etc.).
3/n 🧪

We call this pathway the Pol II Degradation-dependent Apoptotic Response (PDAR).

Our study highlights 3 major surprises about PDAR:

2/n 🧪

awesome work Steve and team!