Stalling of elongating Pol II triggers Ser7 phosphorylation in trans to drive transcription recovery

Shlamovitz, I.; Bao, Y.; Toteva, T.; Crisp, A.; Ye, S.; Wingett, S. W.; Cacioppo, R.; Edmondson, A.; Castiblanco, D.; Boemo, M. A.; Tufegdzic Vidakovic, A.

doi:10.64898/2025.12.04.692291

bioRxiv · 10.64898/2025.12.04.692291

Stalling of elongating Pol II triggers Ser7 phosphorylation in trans to drive transcription recovery

Shlamovitz, I.·Bao, Y.·Toteva, T.·Crisp, A.·Ye, S.·Wingett, S. W.·Cacioppo, R.·Edmondson, A.·Castiblanco, D.·Boemo, M. A.·Tufegdzic Vidakovic, A.

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Abstract

DNA is scattered with obstacles that stall RNA polymerase II (Pol II) and block the production of full-length transcripts. Two mechanisms are known to resolve stalled Pol II: transcription-coupled nucleotide excision repair (TC-NER) and the "last resort" Pol II ubiquitylation-degradation pathway. Here, we uncover a third, distinct mechanism that alerts incoming Pol II molecules to roadblocks ahead and primes them for efficient elongation. We show that transcription stalling triggers GSK3-mediated phosphorylation of Ser7 residues (Ser7P) on the Pol II C-terminal domain. Unexpectedly, this phosphorylation occurs in trans: obstacles in gene bodies induce Ser7P on Pol II complexes at gene beginnings. This modification enables processive transcription while restraining excessive Pol II degradation by the "last resort" pathway. Our findings reveal an adaptive system that preserves transcriptional homeostasis by coordinating polymerase behavior across the gene in response to elongation stress.

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Shlamovitz, I., Bao, Y., Toteva, T., Crisp, A., Ye, S., Wingett, S. W., Cacioppo, R., Edmondson, A., Castiblanco, D., Boemo, M. A., Tufegdzic Vidakovic, A.. 2025-12-05. Stalling of elongating Pol II triggers Ser7 phosphorylation in trans to drive transcription recovery. https://doi.org/10.64898/2025.12.04.692291

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