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

• Published in: Nature communications Vol. 15; no. 1; pp. 4616 - 21
• Main Authors: Walker, Faye M, Sobral, Lays Martin, Danis, Etienne, Sanford, Bridget, Donthula, Sahiti, Balakrishnan, Ilango, Wang, Dong, Pierce, Angela, Karam, Sana D, Kargar, Soudabeh, Serkova, Natalie J, Foreman, Nicholas K, Venkataraman, Sujatha, Dowell, Robin, Vibhakar, Rajeev, Dahl, Nathan A
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 30.05.2024; Nature Portfolio
• Subjects: Animals; Apoptosis; Apoptosis - genetics; Apoptosis - radiation effects; Brain Neoplasms - genetics; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - radiotherapy; Cancer therapies; Cell cycle; Cell Line, Tumor; Chromatin; Combinatorial analysis; DNA damage; DNA repair; DNA Repair - radiation effects; DNA-directed RNA polymerase; Gene expression; Gene Expression Regulation, Neoplastic - radiation effects; Genomes; Glioma; Glioma - genetics; Glioma - metabolism; Glioma - pathology; Glioma - radiotherapy; Glioma cells; Heat shock; Humans; Ionizing radiation; Malignancy; Mice; Pediatrics; Positive Transcriptional Elongation Factor B - genetics; Positive Transcriptional Elongation Factor B - metabolism; Prolongation; Radiation therapy; Regulatory mechanisms (biology); RNA polymerase; RNA polymerase II; RNA Polymerase II - genetics; RNA Polymerase II - metabolism; Survival; Transcription; Transcription, Genetic - radiation effects; Xenograft Model Antitumor Assays; Xenotransplantation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-024-48214-3

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.