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DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis

Author

Listed:
  • Jirina Bartkova

    (Danish Cancer Society)

  • Zuzana Hořejší

    (Danish Cancer Society
    Czech Academy of Sciences)

  • Karen Koed

    (Aarhus University Hospital, Skejby)

  • Alwin Krämer

    (Danish Cancer Society)

  • Frederic Tort

    (Danish Cancer Society)

  • Karsten Zieger

    (Aarhus University Hospital, Skejby)

  • Per Guldberg

    (Danish Cancer Society)

  • Maxwell Sehested

    (University Hospital)

  • Jahn M. Nesland

    (University of Oslo)

  • Claudia Lukas

    (Danish Cancer Society)

  • Torben Ørntoft

    (Aarhus University Hospital, Skejby)

  • Jiri Lukas

    (Danish Cancer Society)

  • Jiri Bartek

    (Danish Cancer Society)

Abstract

During the evolution of cancer, the incipient tumour experiences ‘oncogenic stress’, which evokes a counter-response to eliminate such hazardous cells. However, the nature of this stress remains elusive, as does the inducible anti-cancer barrier that elicits growth arrest or cell death. Here we show that in clinical specimens from different stages of human tumours of the urinary bladder, breast, lung and colon, the early precursor lesions (but not normal tissues) commonly express markers of an activated DNA damage response. These include phosphorylated kinases ATM and Chk2, and phosphorylated histone H2AX and p53. Similar checkpoint responses were induced in cultured cells upon expression of different oncogenes that deregulate DNA replication. Together with genetic analyses, including a genome-wide assessment of allelic imbalances, our data indicate that early in tumorigenesis (before genomic instability and malignant conversion), human cells activate an ATR/ATM-regulated DNA damage response network that delays or prevents cancer. Mutations compromising this checkpoint, including defects in the ATM–Chk2–p53 pathway, might allow cell proliferation, survival, increased genomic instability and tumour progression.

Suggested Citation

  • Jirina Bartkova & Zuzana Hořejší & Karen Koed & Alwin Krämer & Frederic Tort & Karsten Zieger & Per Guldberg & Maxwell Sehested & Jahn M. Nesland & Claudia Lukas & Torben Ørntoft & Jiri Lukas & Jiri B, 2005. "DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis," Nature, Nature, vol. 434(7035), pages 864-870, April.
  • Handle: RePEc:nat:nature:v:434:y:2005:i:7035:d:10.1038_nature03482
    DOI: 10.1038/nature03482
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    Cited by:

    1. 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.
    2. 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.
    3. 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.
    4. Wei Wu & Szymon A. Barwacz & Rahul Bhowmick & Katrine Lundgaard & Marisa M. Gonçalves Dinis & Malgorzata Clausen & Masato T. Kanemaki & Ying Liu, 2023. "Mitotic DNA synthesis in response to replication stress requires the sequential action of DNA polymerases zeta and delta in human cells," Nature Communications, Nature, vol. 14(1), pages 1-17, December.
    5. Abhishek Bharadwaj Sharma & Muhammad Khairul Ramlee & Joel Kosmin & Martin R. Higgs & Amy Wolstenholme & George E. Ronson & Dylan Jones & Daniel Ebner & Noor Shamkhi & David Sims & Paul W. G. Wijnhove, 2023. "C16orf72/HAPSTR1/TAPR1 functions with BRCA1/Senataxin to modulate replication-associated R-loops and confer resistance to PARP disruption," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    6. Simão, Éder M. & Cabral, Heleno B. & Castro, Mauro A.A. & Sinigaglia, Marialva & Mombach, José C.M. & Librelotto, Giovani R., 2010. "Modeling the Human Genome Maintenance network," Physica A: Statistical Mechanics and its Applications, Elsevier, vol. 389(19), pages 4188-4194.
    7. Yukinari Haraoka & Yuki Akieda & Yuri Nagai & Chihiro Mogi & Tohru Ishitani, 2022. "Zebrafish imaging reveals TP53 mutation switching oncogene-induced senescence from suppressor to driver in primary tumorigenesis," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    8. Jean-Philippe Coppé & Christopher K Patil & Francis Rodier & Yu Sun & Denise P Muñoz & Joshua Goldstein & Peter S Nelson & Pierre-Yves Desprez & Judith Campisi, 2008. "Senescence-Associated Secretory Phenotypes Reveal Cell-Nonautonomous Functions of Oncogenic RAS and the p53 Tumor Suppressor," PLOS Biology, Public Library of Science, vol. 6(12), pages 1-1, December.

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