IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v15y2024i1d10.1038_s41467-024-48214-3.html
   My bibliography  Save this article

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

Author

Listed:
  • 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
    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
    Children’s Hospital Colorado
    University of Colorado School of Medicine)

  • Sujatha Venkataraman

    (University of Colorado School of Medicine)

  • Robin Dowell

    (University of Colorado
    University of Colorado)

  • Rajeev Vibhakar

    (University of Colorado School of Medicine
    Children’s Hospital Colorado
    University of Colorado School of Medicine)

  • Nathan A. Dahl

    (University of Colorado School of Medicine
    Children’s Hospital Colorado)

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.

Suggested Citation

  • 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 & Nicho, 2024. "Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
  • Handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48214-3
    DOI: 10.1038/s41467-024-48214-3
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-024-48214-3
    File Function: Abstract
    Download Restriction: no

    File URL: https://libkey.io/10.1038/s41467-024-48214-3?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Zhiyuan Yang & Qingwei Zhu & Kunxin Luo & Qiang Zhou, 2001. "The 7SK small nuclear RNA inhibits the CDK9/cyclin T1 kinase to control transcription," Nature, Nature, vol. 414(6861), pages 317-322, November.
    2. Jian Chen & Yanjiao Li & Tzong-Shiue Yu & Renée M. McKay & Dennis K. Burns & Steven G. Kernie & Luis F. Parada, 2012. "A restricted cell population propagates glioblastoma growth after chemotherapy," Nature, Nature, vol. 488(7412), pages 522-526, August.
    3. Jeremy Schwartzentruber & Andrey Korshunov & Xiao-Yang Liu & David T. W. Jones & Elke Pfaff & Karine Jacob & Dominik Sturm & Adam M. Fontebasso & Dong-Anh Khuong Quang & Martje Tönjes & Volker Hovesta, 2012. "Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma," Nature, Nature, vol. 482(7384), pages 226-231, February.
    4. Tyler E. Miller & Brian B. Liau & Lisa C. Wallace & Andrew R. Morton & Qi Xie & Deobrat Dixit & Daniel C. Factor & Leo J. Y. Kim & James J. Morrow & Qiulian Wu & Stephen C. Mack & Christopher G. Huber, 2017. "Transcription elongation factors represent in vivo cancer dependencies in glioblastoma," Nature, Nature, vol. 547(7663), pages 355-359, July.
    5. Christopher J. Lord & Alan Ashworth, 2012. "The DNA damage response and cancer therapy," Nature, Nature, vol. 481(7381), pages 287-294, January.
    6. Sheila K. Singh & Cynthia Hawkins & Ian D. Clarke & Jeremy A. Squire & Jane Bayani & Takuichiro Hide & R. Mark Henkelman & Michael D. Cusimano & Peter B. Dirks, 2004. "Identification of human brain tumour initiating cells," Nature, Nature, vol. 432(7015), pages 396-401, November.
    7. Nicholas J. Fuda & M. Behfar Ardehali & John T. Lis, 2009. "Defining mechanisms that regulate RNA polymerase II transcription in vivo," Nature, Nature, vol. 461(7261), pages 186-192, September.
    8. Anastasios Liakos & Dimitris Konstantopoulos & Matthieu D. Lavigne & Maria Fousteri, 2020. "Continuous transcription initiation guarantees robust repair of all transcribed genes and regulatory regions," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    9. Joshua M. Dempster & Clare Pacini & Sasha Pantel & Fiona M. Behan & Thomas Green & John Krill-Burger & Charlotte M. Beaver & Scott T. Younger & Victor Zhivich & Hanna Najgebauer & Felicity Allen & Ema, 2019. "Agreement between two large pan-cancer CRISPR-Cas9 gene dependency data sets," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    10. Jeremy Schwartzentruber & Andrey Korshunov & Xiao-Yang Liu & David T. W. Jones & Elke Pfaff & Karine Jacob & Dominik Sturm & Adam M. Fontebasso & Dong-Anh Khuong Quang & Martje Tönjes & Volker Hovesta, 2012. "Correction: Corrigendum: Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma," Nature, Nature, vol. 484(7392), pages 130-130, April.
    11. Shideng Bao & Qiulian Wu & Roger E. McLendon & Yueling Hao & Qing Shi & Anita B. Hjelmeland & Mark W. Dewhirst & Darell D. Bigner & Jeremy N. Rich, 2006. "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response," Nature, Nature, vol. 444(7120), pages 756-760, December.
    12. Lei Guo & Jia Li & Hongxiang Zeng & Anna G. Guzman & Tingting Li & Minjung Lee & Yubin Zhou & Margaret A. Goodell & Clifford Stephan & Peter J. A. Davies & Mark A Dawson & Deqiang Sun & Yun Huang, 2020. "A combination strategy targeting enhancer plasticity exerts synergistic lethality against BETi-resistant leukemia cells," Nature Communications, Nature, vol. 11(1), pages 1-16, December.
    13. Stephen P. Jackson & Jiri Bartek, 2009. "The DNA-damage response in human biology and disease," Nature, Nature, vol. 461(7267), pages 1071-1078, October.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Jun Liu & Xiaoying Wang & Ann T. Chen & Xingchun Gao & Benjamin T. Himes & Hongyi Zhang & Zeming Chen & Jianhui Wang & Wendy C. Sheu & Gang Deng & Yang Xiao & Pan Zou & Shenqi Zhang & Fuyao Liu & Yong, 2022. "ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    2. Michelle M. Kameda-Smith & Helen Zhu & En-Ching Luo & Yujin Suk & Agata Xella & Brian Yee & Chirayu Chokshi & Sansi Xing & Frederick Tan & Raymond G. Fox & Ashley A. Adile & David Bakhshinyan & Kevin , 2022. "Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. Tatenda Mahlokozera & Bhuvic Patel & Hao Chen & Patrick Desouza & Xuan Qu & Diane D. Mao & Daniel Hafez & Wei Yang & Rukayat Taiwo & Mounica Paturu & Afshin Salehi & Amit D. Gujar & Gavin P. Dunn & Ni, 2021. "Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Paweł Wańkowicz & Przemysław Nowacki & Bogusław Machaliński & Dorota Rogińska, 2019. "Biomarkers of Cancer Stem Cells in Glioblastoma Multiforme and Histological Picture of Cancer," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 23(3), pages 17365-17368, December.
    5. Ravinder K. Bahia & Xiaoguang Hao & Rozina Hassam & Orsolya Cseh & Danielle A. Bozek & H. Artee Luchman & Samuel Weiss, 2023. "Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    6. Fei Li & Yizhe Wang & Inah Hwang & Ja-Young Jang & Libo Xu & Zhong Deng & Eun Young Yu & Yiming Cai & Caizhi Wu & Zhenbo Han & Yu-Han Huang & Xiangao Huang & Ling Zhang & Jun Yao & Neal F. Lue & Paul , 2023. "Histone demethylase KDM2A is a selective vulnerability of cancers relying on alternative telomere maintenance," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    7. Francesco Antonica & Lucia Santomaso & Davide Pernici & Linda Petrucci & Giuseppe Aiello & Alessandro Cutarelli & Luciano Conti & Alessandro Romanel & Evelina Miele & Toma Tebaldi & Luca Tiberi, 2022. "A slow-cycling/quiescent cells subpopulation is involved in glioma invasiveness," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Min Kyung Lee & Nasim Azizgolshani & Joshua A. Shapiro & Lananh N. Nguyen & Fred W. Kolling & George J. Zanazzi & Hildreth Robert Frost & Brock C. Christensen, 2024. "Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Hanrui Zhang & Julian Kreis & Sven-Eric Schelhorn & Heike Dahmen & Thomas Grombacher & Michael Zühlsdorf & Frank T. Zenke & Yuanfang Guan, 2023. "Mapping combinatorial drug effects to DNA damage response kinase inhibitors," Nature Communications, Nature, vol. 14(1), pages 1-8, December.
    10. Weiwei Lin & Rui Niu & Seong-Min Park & Yan Zou & Sung Soo Kim & Xue Xia & Songge Xing & Qingshan Yang & Xinhong Sun & Zheng Yuan & Shuchang Zhou & Dongya Zhang & Hyung Joon Kwon & Saewhan Park & Chan, 2023. "IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    11. Sean A. Misek & Aaron Fultineer & Jeremie Kalfon & Javad Noorbakhsh & Isabella Boyle & Priyanka Roy & Joshua Dempster & Lia Petronio & Katherine Huang & Alham Saadat & Thomas Green & Adam Brown & John, 2024. "Germline variation contributes to false negatives in CRISPR-based experiments with varying burden across ancestries," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    12. Zita Gál & Stavroula Boukoura & Kezia Catharina Oxe & Sara Badawi & Blanca Nieto & Lea Milling Korsholm & Sille Blangstrup Geisler & Ekaterina Dulina & Anna Vestergaard Rasmussen & Christina Dahl & We, 2024. "Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    13. Ilaria Rosso & Corey Jones-Weinert & Francesca Rossiello & Matteo Cabrini & Silvia Brambillasca & Leonel Munoz-Sagredo & Zeno Lavagnino & Emanuele Martini & Enzo Tedone & Massimiliano Garre’ & Julio A, 2023. "Alternative lengthening of telomeres (ALT) cells viability is dependent on C-rich telomeric RNAs," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    14. Ross A. Cordiner & Yuhui Dou & Rune Thomsen & Andrii Bugai & Sander Granneman & Torben Heick Jensen, 2023. "Temporal-iCLIP captures co-transcriptional RNA-protein interactions," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    15. Ci Fu & Xiang Zhang & Amanda O. Veri & Kali R. Iyer & Emma Lash & Alice Xue & Huijuan Yan & Nicole M. Revie & Cassandra Wong & Zhen-Yuan Lin & Elizabeth J. Polvi & Sean D. Liston & Benjamin VanderSlui, 2021. "Leveraging machine learning essentiality predictions and chemogenomic interactions to identify antifungal targets," Nature Communications, Nature, vol. 12(1), pages 1-18, December.
    16. Daipayan Banerjee & Kurt Langberg & Salar Abbas & Eric Odermatt & Praveen Yerramothu & Martin Volaric & Matthew A. Reidenbach & Kathy J. Krentz & C. Dustin Rubinstein & David L. Brautigan & Tarek Abba, 2021. "A non-canonical, interferon-independent signaling activity of cGAMP triggers DNA damage response signaling," Nature Communications, Nature, vol. 12(1), pages 1-24, December.
    17. Zhdanov, Vladimir P., 2011. "Periodic perturbation of the bistable kinetics of gene expression," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 390(1), pages 57-64.
    18. Kaori Asamitsu & Takatsugu Hirokawa & Takashi Okamoto, 2017. "MD simulation of the Tat/Cyclin T1/CDK9 complex revealing the hidden catalytic cavity within the CDK9 molecule upon Tat binding," PLOS ONE, Public Library of Science, vol. 12(2), pages 1-14, February.
    19. Ryan Damme & Kongpan Li & Minjie Zhang & Jianhui Bai & Wilson H. Lee & Joseph D. Yesselman & Zhipeng Lu & Willem A. Velema, 2022. "Chemical reversible crosslinking enables measurement of RNA 3D distances and alternative conformations in cells," Nature Communications, Nature, vol. 13(1), pages 1-13, December.
    20. Roberto Bandiera & Rebecca E. Wagner & Thiago Britto-Borges & Christoph Dieterich & Sabine Dietmann & Susanne Bornelöv & Michaela Frye, 2021. "RN7SK small nuclear RNA controls bidirectional transcription of highly expressed gene pairs in skin," Nature Communications, Nature, vol. 12(1), pages 1-14, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:15:y:2024:i:1:d:10.1038_s41467-024-48214-3. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.