Nature 434, 864-870 (14 April 2005) | doi:10.1038/nature03482; Received 15 December 2004; Accepted 18 February 2005

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

Jirina Bartkova1, Zuzana Hor caronejs caroní1,5, Karen Koed2, Alwin Krämer1, Frederic Tort1, Karsten Zieger2, Per Guldberg1, Maxwell Sehested3, Jahn M. Nesland4, Claudia Lukas1, Torben Ørntoft2, Jiri Lukas1 & Jiri Bartek1

  1. Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark
  2. Department of Clinical Biochemistry, Aarhus University Hospital, Skejby, DK-8200 Aarhus N, Denmark
  3. Department of Pathology, University Hospital, Frederik V's Vej 11, DK-2100 Copenhagen, Denmark
  4. Department of Pathology, The Norwegian Radium Hospital, University of Oslo, Ullernchausseen 70-0310 Oslo, Norway
  5. Institute of Molecular Genetics, Czech Academy of Sciences, Flemingovo nam. 2, Praha 6, CZ-16637, Czech Republic

Correspondence to: Jirina Bartkova1Jiri Bartek1 Correspondence and requests for materials should be addressed to J.B. (Email:


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.