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

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 and Binghui Shen ()
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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
Zhigang Guo: City of Hope National Medical Center and Beckman Research Institute
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

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: 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.

Date: 2012
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DOI: 10.1038/ncomms1825

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