Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy

Faye M. Walker, Lays Martin Sobral, Etienne Danis, Bridget Sanford, Sahiti Donthula, Ilango Balakrishnan, Dong Wang, Angela Pierce, Sana D. Karam, Soudabeh Kargar, Natalie J. Serkova, Nicholas K. Foreman, Sujatha Venkataraman, Robin Dowell, Rajeev Vibhakar and Nathan A. Dahl ()
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Faye M. Walker: University of Colorado School of Medicine
Lays Martin Sobral: University of Colorado School of Medicine
Etienne Danis: University of Colorado School of Medicine
Bridget Sanford: University of Colorado School of Medicine
Sahiti Donthula: University of Colorado School of Medicine
Ilango Balakrishnan: University of Colorado School of Medicine
Dong Wang: University of Colorado School of Medicine
Angela Pierce: University of Colorado School of Medicine
Sana D. Karam: University of Colorado School of Medicine
Soudabeh Kargar: University of Colorado School of Medicine
Natalie J. Serkova: University of Colorado School of Medicine
Nicholas K. Foreman: University of Colorado School of Medicine
Sujatha Venkataraman: University of Colorado School of Medicine
Robin Dowell: University of Colorado
Rajeev Vibhakar: University of Colorado School of Medicine
Nathan A. Dahl: University of Colorado School of Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-21

Abstract: Abstract Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. P-TEFb-mediated pause-release of RNA polymerase II (Pol II) is a conserved regulatory mechanism for synchronous transcriptional induction in response to heat shock, but this pro-survival role has not been examined in the applied context of cancer therapy. Using model systems of pediatric high-grade glioma, we show that rapid genome-wide reorganization of active chromatin facilitates P-TEFb-mediated nascent transcriptional induction within hours of exposure to therapeutic ionizing radiation. Concurrent inhibition of P-TEFb disrupts this chromatin reorganization and blunts transcriptional induction, abrogating key adaptive programs such as DNA damage repair and cell cycle regulation. This combination demonstrates a potent, synergistic therapeutic potential agnostic of glioma subtype, leading to a marked induction of tumor cell apoptosis and prolongation of xenograft survival. These studies reveal a central role for P-TEFb underpinning the early adaptive response to radiotherapy, opening avenues for combinatorial treatment in these lethal malignancies.

Date: 2024
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DOI: 10.1038/s41467-024-48214-3

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