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.

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