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When DNA damage prevents cancer

Nature Reviews Cancer volume 7, page 3 (2007)Cite this article

The groups show that overexpression of the oncogenes MOS , CDC6 , CCNE1 (which encodes cyclin E) and activated HRAS in human fibroblast cell lines results in OIS. Cells that showed features of OIS correlated with the activation of two key DDR signalling pathways that involve the kinases ataxia-telangiectasia and rad3-related (ATR) and ataxia-telangiectasia mutated (ATM). Inhibition of ATR-dependent and ATM-dependent DDR pathway members, such as CHK2, p53 and ATM itself, abrogated OIS in these cells, indicating that efficient DDR pathway activation is required for the establishment and maintenance of OIS. This was confirmed in vivo when immunodeficient mice injected with Chk2−/− mouse embryonic fibroblasts (MEFs) that overexpressed activated Hras formed tumours, unlike those injected with wild-type MEFs that expressed activated Hras. Larger and more invasive tumours were also observed when immunodeficient mice were injected with PDVC57 mouse tumour cells in which ATM was inhibited.

So, what type of DNA damage activates DDR signalling during OIS? The groups show that cells that overexpressed MOS, CDC6, CCNE1 or activated HRAS placed in non-replicative conditions did not activate DDR signalling pathways or undergo OIS. Additionally, d'Adda di Fagagna and colleagues show that activated HRAS overexpression leads to DNA hyper-replication, followed by the activation of DDR signalling pathways and then OIS. Both groups show that DNA damage occurs in replicating cells, in which oncogene overexpression results in aberrant replication dynamics and replication-fork instability. Consequently, DNA strand breaks occur, which lead to genomic instability and the activation of ATM-dependent and ATR-dependent DDR signalling pathways.

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References

ORIGINAL RESEARCH PAPER

  1. Bartkova, J. et al. Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature (30 November 2006) (doi: 10.1038/nature05268)

  2. Di Micco, R. et al. Oncogene-induced senescence is a DNA damage checkpoint response triggered by DNA hyper-replication. Nature (30 November 2006) (doi: 10.1038/nature05327)

FURTHER READING

  1. Sieber, O. M. et al. Genomic instability — the engine of tumorigenesis?. Nature Rev. Cancer 3, 701–708 (2003)

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Authors
  1. Gemma Alderton
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Alderton, G. When DNA damage prevents cancer. Nat Rev Cancer 7, 3 (2007). https://doi.org/10.1038/nrc2056

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