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XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY
Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-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...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Oxford University Press
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260099/ http://dx.doi.org/10.1093/neuonc/noad073.302 |
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author | Walker, Faye Sobral, Lays Martin Danis, Etienne Sanford, Bridget Balakrishnan, Ilango Wang, Dong Pierce, Angela Karam, Sana Serkova, Natalie Foreman, Nicholas Venkataraman, Sujatha Dowell, Robin Vibhakar, Rajeev Dahl, Nathan |
author_facet | Walker, Faye Sobral, Lays Martin Danis, Etienne Sanford, Bridget Balakrishnan, Ilango Wang, Dong Pierce, Angela Karam, Sana Serkova, Natalie Foreman, Nicholas Venkataraman, Sujatha Dowell, Robin Vibhakar, Rajeev Dahl, Nathan |
author_sort | Walker, Faye |
collection | PubMed |
description | Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-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 a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA 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 PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies. |
format | Online Article Text |
id | pubmed-10260099 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2023 |
publisher | Oxford University Press |
record_format | MEDLINE/PubMed |
spelling | pubmed-102600992023-06-13 XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY Walker, Faye Sobral, Lays Martin Danis, Etienne Sanford, Bridget Balakrishnan, Ilango Wang, Dong Pierce, Angela Karam, Sana Serkova, Natalie Foreman, Nicholas Venkataraman, Sujatha Dowell, Robin Vibhakar, Rajeev Dahl, Nathan Neuro Oncol Final Category: Radiation Oncology - XRT Dynamic regulation of gene expression is fundamental for cellular adaptation to exogenous stressors. PTEFb-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 a combination of ChIP-, ATAC-, and RNA-seq in model systems of diffuse intrinsic pontine glioma and other pediatric high-grade gliomas, we observe a rapid genome-wide reorganization of active chromatin within hours of exposure to therapeutic ionizing radiation. This redistribution facilitates PTEFb-mediated pause-release of Pol II to drive nascent transcriptional induction of canonical DNA damage response programs. Concurrent inhibition of PTEFb imparts a transcription elongation defect, disrupting this chromatin reorganization and blunting transcriptional induction. Functionally, concurrent PTEFb inhibition abrogates key adaptive programs such as DNA 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 PTEFb underpinning the early adaptive response to radiotherapy, opening new avenues for combinatorial treatment in these lethal malignancies. Oxford University Press 2023-06-12 /pmc/articles/PMC10260099/ http://dx.doi.org/10.1093/neuonc/noad073.302 Text en © The Author(s) 2023. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. https://creativecommons.org/licenses/by-nc/4.0/This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial License (https://creativecommons.org/licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact journals.permissions@oup.com |
spellingShingle | Final Category: Radiation Oncology - XRT Walker, Faye Sobral, Lays Martin Danis, Etienne Sanford, Bridget Balakrishnan, Ilango Wang, Dong Pierce, Angela Karam, Sana Serkova, Natalie Foreman, Nicholas Venkataraman, Sujatha Dowell, Robin Vibhakar, Rajeev Dahl, Nathan XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title | XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title_full | XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title_fullStr | XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title_full_unstemmed | XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title_short | XRT-06. RAPID PTEFB-DEPENDENT TRANSCRIPTIONAL REORGANIZATION UNDERPINS THE GLIOMA ADAPTIVE RESPONSE TO RADIOTHERAPY |
title_sort | xrt-06. rapid ptefb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy |
topic | Final Category: Radiation Oncology - XRT |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10260099/ http://dx.doi.org/10.1093/neuonc/noad073.302 |
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