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Increased global transcription activity as a mechanism of replication stress in cancer

Author

Listed:
  • Panagiotis Kotsantis

    (Institute of Cancer and Genomic Sciences, University of Birmingham)

  • Lara Marques Silva

    (Sir William Dunn School of Pathology, University of Oxford)

  • Sarah Irmscher

    (Sir William Dunn School of Pathology, University of Oxford)

  • Rebecca M. Jones

    (Institute of Cancer and Genomic Sciences, University of Birmingham)

  • Lisa Folkes

    (CRUK/MRC Oxford Institute for Radiation Oncology, University of Oxford)

  • Natalia Gromak

    (Sir William Dunn School of Pathology, University of Oxford)

  • Eva Petermann

    (Institute of Cancer and Genomic Sciences, University of Birmingham)

Abstract

Cancer is a disease associated with genomic instability that often results from oncogene activation. This in turn leads to hyperproliferation and replication stress. However, the molecular mechanisms that underlie oncogene-induced replication stress are still poorly understood. Oncogenes such as HRASV12 promote proliferation by upregulating general transcription factors to stimulate RNA synthesis. Here we investigate whether this increase in transcription underlies oncogene-induced replication stress. We show that in cells overexpressing HRASV12, elevated expression of the general transcription factor TATA-box binding protein (TBP) leads to increased RNA synthesis, which together with R-loop accumulation results in replication fork slowing and DNA damage. Furthermore, overexpression of TBP alone causes the hallmarks of oncogene-induced replication stress, including replication fork slowing, DNA damage and senescence. Consequently, we reveal that increased transcription can be a mechanism of oncogene-induced DNA damage, providing a molecular link between upregulation of the transcription machinery and genomic instability in cancer.

Suggested Citation

  • Panagiotis Kotsantis & Lara Marques Silva & Sarah Irmscher & Rebecca M. Jones & Lisa Folkes & Natalia Gromak & Eva Petermann, 2016. "Increased global transcription activity as a mechanism of replication stress in cancer," Nature Communications, Nature, vol. 7(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms13087
    DOI: 10.1038/ncomms13087
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    1. Silvia Peripolli & Leticia Meneguello & Chiara Perrod & Tanya Singh & Harshil Patel & Sazia T. Rahman & Koshiro Kiso & Peter Thorpe & Vincenzo Calvanese & Cosetta Bertoli & Robertus A. M. de Bruin, 2024. "Oncogenic c-Myc induces replication stress by increasing cohesins chromatin occupancy in a CTCF-dependent manner," Nature Communications, Nature, vol. 15(1), pages 1-11, December.
    2. Chia-Yu Guh & Hong-Jhih Shen & Liv WeiChien Chen & Pei-Chen Chiu & I-Hsin Liao & Chen-Chia Lo & Yunfei Chen & Yu-Hung Hsieh & Ting-Chia Chang & Chien-Ping Yen & Yi-Yun Chen & Tom Wei-Wu Chen & Liuh-Yo, 2022. "XPF activates break-induced telomere synthesis," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    3. David Rombaut & Carine Lefèvre & Tony Rached & Sabrina Bondu & Anne Letessier & Raphael M. Mangione & Batoul Farhat & Auriane Lesieur-Pasquier & Daisy Castillo-Guzman & Ismael Boussaid & Chloé Friedri, 2024. "Accelerated DNA replication fork speed due to loss of R-loops in myelodysplastic syndromes with SF3B1 mutation," Nature Communications, Nature, vol. 15(1), pages 1-20, December.
    4. Daniel Gómez-Cabello & George Pappas & Diana Aguilar-Morante & Christoffel Dinant & Jiri Bartek, 2022. "CtIP-dependent nascent RNA expression flanking DNA breaks guides the choice of DNA repair pathway," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    5. Taichi Igarashi & Marianne Mazevet & Takaaki Yasuhara & Kimiyoshi Yano & Akifumi Mochizuki & Makoto Nishino & Tatsuya Yoshida & Yukihiro Yoshida & Nobuhiko Takamatsu & Akihide Yoshimi & Kouya Shiraish, 2023. "An ATR-PrimPol pathway confers tolerance to oncogenic KRAS-induced and heterochromatin-associated replication stress," Nature Communications, Nature, vol. 14(1), pages 1-22, December.
    6. Shaun Scaramuzza & Rebecca M. Jones & Martina Muste Sadurni & Alicja Reynolds-Winczura & Divyasree Poovathumkadavil & Abigail Farrell & Toyoaki Natsume & Patricia Rojas & Cyntia Fernandez Cuesta & Mas, 2023. "TRAIP resolves DNA replication-transcription conflicts during the S-phase of unperturbed cells," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    7. Tomoko Yamamori Morita & Jie Yu & Yukie Kashima & Ryo Kamata & Gaku Yamamoto & Tatsunori Minamide & Chiaki Mashima & Miyuki Yoshiya & Yuta Sakae & Toyohiro Yamauchi & Yumi Hakozaki & Shun-ichiro Kagey, 2023. "CDC7 inhibition induces replication stress-mediated aneuploid cells with an inflammatory phenotype sensitizing tumors to immune checkpoint blockade," Nature Communications, Nature, vol. 14(1), pages 1-21, December.
    8. Hervé Técher & Diyavarshini Gopaul & Jonathan Heuzé & Nail Bouzalmad & Baptiste Leray & Audrey Vernet & Clément Mettling & Jérôme Moreaux & Philippe Pasero & Yea-Lih Lin, 2024. "MRE11 and TREX1 control senescence by coordinating replication stress and interferon signaling," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    9. Elias Einig & Chao Jin & Valentina Andrioletti & Boris Macek & Nikita Popov, 2023. "RNAPII-dependent ATM signaling at collisions with replication forks," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    10. Ting Zhang & Carsten Künne & Dong Ding & Stefan Günther & Xinyue Guo & Yonggang Zhou & Xuejun Yuan & Thomas Braun, 2022. "Replication collisions induced by de-repressed S-phase transcription are connected with malignant transformation of adult stem cells," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

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