This was fantastic work led by @ivavitz.bsky.social , Yu Bao, Tea Toteva and Alastair Crisp. Also a wonderful collaboration with Mike Boemo's lab. 🧪🧬🧫

If the obstacles are not fixed by the time these Ser7-hyper-phosphorylated polymerases reach them, Ser7p protects these Pol II molecules from ubiquitylation and degradation to salvage a minimal pool of Pol II needed for recovery, preventing irreversible transcription shutdown.

Overall, we propose that stalling of elongating Pol II in gene bodies triggers Ser7p in trans, on polymerases just entering elongation, to "warn" them there are obstacles lying ahead.

We identify GSK3 as a Ser7 kinase, which is interesting in light of previous work by Kornblihtt and Marteijn labs implicating GSK3 in regulation of stalled Pol II.

Ser7p is a universal hallmark of stalled transcription: fundamentally different obstacles to elongating Pol II all cause induction of Ser7p. We find this is likely because they all cause Pol II backtracking - and Pol II backtracking alone is sufficient to induce profound Ser7p upregulation.

Mechanistically, Ser7p inhibits excessive degradation of Pol II by the Last resort pathway, and protects a minimal reserve of Pol II molecules needed for transcription recovery.

Pol II stalling is known to trigger two pathways: transcription-coupled NER (TC-NER) and the last resort ubiquitylation-degradation of Pol II. We find Ser7p represents a third pathway altogether. All three pathways are needed for transcription recovery after DNA damage.

Ser7p remains the least understood Pol II phospho-mark, with unknown function on protein coding genes. We find Ser7p is required for productive Pol II elongation and for transcription recovery after DNA damage.

We discovered that stalling of elongating Pol II in gene bodies triggers hyper-phosphorylation of Ser7 at the Pol II CTD. To our surprise, this didn't happen directly on stalled Pol II molecules but at a remote part of the gene - near the gene beginning, in the early elongation zone!

This was a fantastic team work led by Roberta Cacioppo, Alexander Gillis, Ivan Shlamovitz and Andrew Zeller. Also take a look at a complementary work by Svejstrup Lab: www.sciencedirect.com/science/arti...

We conclude that ARMC5 and Integrator phosphatase work in parallel to monitor the quantity and quality of Pol II complexes before they are licenced to enter elongation.

We conduct a synthetic lethality mini-screen and identify Integrator phosphatese compensates for the loss of ARMC5! When both Integrator phosphatase and ARMC5 are missing, excessive Pol II enters early elongation, but many of these are transcription-incompetent and fail to reach gene ends.

Loss of ARMC5 causes profound accumulation of Pol II both off-DNA and at gene beginnings, but not in gene bodies. Something else is preventing all this excess Pol II at initial stages of transcription to proceed into elongation. What is it?

But why would cells ubiquitylate and destroy promoter-proximal Pol II? We find that ARMC5 targets "defective" Pol II complexes! So what happens to transcription if this pathway is lost?