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

Jirina Bartkova; Zuzana Horejsí; Karen Koed; Alwin Krämer; Frederic Tort; Karsten Zieger; Per Guldberg; Maxwell Sehested; Jahn M Nesland; Claudia Lukas; Torben Ørntoft; Jiri Lukas; Jiri Bartek

doi:10.1038/nature03482

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

Nature. 2005 Apr 14;434(7035):864-70. doi: 10.1038/nature03482.

Authors

Jirina Bartkova¹, Zuzana Horejsí, Karen Koed, Alwin Krämer, Frederic Tort, Karsten Zieger, Per Guldberg, Maxwell Sehested, Jahn M Nesland, Claudia Lukas, Torben Ørntoft, Jiri Lukas, Jiri Bartek

Affiliation

¹ Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, Strandboulevarden 49, DK-2100 Copenhagen, Denmark. jb@cancer.dk

PMID: 15829956
DOI: 10.1038/nature03482

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Allelic Imbalance / genetics
Cell Cycle
Cell Cycle Proteins / genetics
Cell Cycle Proteins / metabolism
Cell Line, Tumor
Cell Transformation, Neoplastic* / genetics
Checkpoint Kinase 2
Cyclin E / genetics
Cyclin E / metabolism
DNA Damage* / genetics
DNA-Binding Proteins / genetics
DNA-Binding Proteins / metabolism
E2F Transcription Factors
Enzyme Activation
Genes, p53 / genetics
Genomic Instability
Humans
Mutation / genetics
Neoplasms / enzymology
Neoplasms / genetics
Neoplasms / pathology*
Neoplasms / prevention & control*
Oncogenes / genetics
Oncogenes / physiology
Phosphorylation
Polymorphism, Single Nucleotide / genetics
Protein Serine-Threonine Kinases / metabolism
Signal Transduction
Transcription Factors / genetics
Transcription Factors / metabolism
Urinary Bladder Neoplasms / enzymology
Urinary Bladder Neoplasms / genetics
Urinary Bladder Neoplasms / metabolism
Urinary Bladder Neoplasms / pathology
cdc25 Phosphatases / genetics
cdc25 Phosphatases / metabolism

Substances

Cell Cycle Proteins
Cyclin E
DNA-Binding Proteins
E2F Transcription Factors
Transcription Factors
Checkpoint Kinase 2
CHEK2 protein, human
Protein Serine-Threonine Kinases
CDC25A protein, human
cdc25 Phosphatases