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Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression

Author

Listed:
  • Li Zheng

    (City of Hope National Medical Center and Beckman Research Institute)

  • Huifang Dai

    (City of Hope National Medical Center and Beckman Research Institute)

  • Mian Zhou

    (City of Hope National Medical Center and Beckman Research Institute)

  • Xiaojin Li

    (City of Hope National Medical Center and Beckman Research Institute)

  • Changwei Liu

    (City of Hope National Medical Center and Beckman Research Institute
    Institute of Genetics, College of Life Sciences, Zhejiang University)

  • Zhigang Guo

    (City of Hope National Medical Center and Beckman Research Institute
    Present address: College of Life Sciences, Nanjing Normal University, China.)

  • Xiwei Wu

    (City of Hope National Medical Center and Beckman Research Institute)

  • Jun Wu

    (City of Hope National Medical Center and Beckman Research Institute)

  • Charles Wang

    (City of Hope National Medical Center and Beckman Research Institute)

  • John Zhong

    (University of Southern California)

  • Qin Huang

    (City of Hope National Medical Center and Beckman Research Institute)

  • Julio Garcia-Aguilar

    (City of Hope National Medical Center and Beckman Research Institute)

  • Gerd P. Pfeifer

    (City of Hope National Medical Center and Beckman Research Institute)

  • Binghui Shen

    (City of Hope National Medical Center and Beckman Research Institute
    Institute of Genetics, College of Life Sciences, Zhejiang University)

Abstract

Mutations in genes involved in DNA replication, such as flap endonuclease 1 (FEN1), can cause single-stranded DNA breaks (SSBs) and subsequent collapse of DNA replication forks leading to DNA replication stresses. Persistent replication stresses normally induce p53-mediated senescence or apoptosis to prevent tumour progression. It is unclear how some mutant cells can overcome persistent replication stresses and bypass the p53-mediated pathways to develop malignancy. Here we show that polyploidy, which is often observed in human cancers, leads to overexpression of BRCA1, p19arf and other DNA repair genes in FEN1 mutant cells. This overexpression triggers SSB repair and non-homologous end-joining pathways to increase DNA repair activity, but at the cost of frequent chromosomal translocations. Meanwhile, DNA methylation silences p53 target genes to bypass the p53-mediated senescence and apoptosis. These molecular changes rewire DNA damage response and repair gene networks in polyploid tumour cells, enabling them to escape replication stress-induced senescence barriers.

Suggested Citation

  • Li Zheng & Huifang Dai & Mian Zhou & Xiaojin Li & Changwei Liu & Zhigang Guo & Xiwei Wu & Jun Wu & Charles Wang & John Zhong & Qin Huang & Julio Garcia-Aguilar & Gerd P. Pfeifer & Binghui Shen, 2012. "Polyploid cells rewire DNA damage response networks to overcome replication stress-induced barriers for tumour progression," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms1825
    DOI: 10.1038/ncomms1825
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    Cited by:

    1. Emilien Nicolas & Paul Simion & Marc Guérineau & Matthieu Terwagne & Mathilde Colinet & Julie Virgo & Maxime Lingurski & Anaïs Boutsen & Marc Dieu & Bernard Hallet & Karine Doninck, 2023. "Horizontal acquisition of a DNA ligase improves DNA damage tolerance in eukaryotes," Nature Communications, Nature, vol. 14(1), pages 1-14, December.

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