Editors' ChoiceCancer Biology

Connecting Senescence to DNA Damage Response

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Science's STKE  05 Dec 2006:
Vol. 2006, Issue 364, pp. tw405
DOI: 10.1126/stke.3642006tw405

The body has various mechanisms to prevent the progression from preneoplastic lesion to full neoplasia. One of these is oncogene-induced senescence or withdrawal from the cell cycle. Two groups (Bartkova et al. and Di Micco et al.) now provide evidence that certain oncogenes trigger DNA replication stress and activation of the DNA damage checkpoint response and that activation of the checkpoint response is essential for the observed senescence. Bartkova et al. investigated senescence induced by Mos (an activator of the mitogen-activated protein kinase pathway), Cdc6 (a DNA replication licensing factor), and cyclin E (a protein involved in the cell cycle) in various human diploid cells. In each case, the cells exhibited activation of the DNA damage checkpoint and senescence. If the activity of ATM--a kinase critical to the DNA damage checkpoint response--was blocked by siRNA or pharmacological agents, then senescence was prevented. DNA labeling experiments indicated that the oncogenes triggered the formation of prematurely terminated DNA replication forks, which was the likely mechanism by which double-stranded breaks formed that triggered the DNA damage response. Di Micco et al. provide evidence linking the DNA damage checkpoint response to Ras-induced senescence. Cells undergoing oncogene-induced senescence exhibited activation of the DNA damage checkpoint response. Cells in which checkpoint kinase 2 (CHK2) activity was diminished (by knockout or RNA interference) were more susceptible to Ras-induced transformation and continued to proliferate. Ras triggered a proliferative burst and the cells that subsequently underwent senescence exhibited partly replicated DNA. Bartkova et al. found that there is a correlation in colon adenoma samples between the appearance of markers for senescence and activation of the DNA damage checkpoint, and that progression to carcinoma correlated with a decrease in these two processes. Both groups looked at mouse models of tumorigenesis. Bartkova et al. found that injection of a ras-transformed tumor line into mice in which the activity of ATM was decreased led to the formation of larger and more invasive tumors. Di Micco et al. showed that chemicals that are associated with the induction of Ras mutations in mouse skin cause cellular proliferation and activation of the DNA damage response. It appears that the proliferation triggered by oncogenes can lead to DNA stress, which triggers the DNA damage response, allowing the body to prevent tumor progression.

J. Bartkova, N. Rezaei, M. Liontos, P. Karakaidos, D. Kletsas, N. Issaeva, L.-V. F. Vassiliou, E. Kolettas, K. Niforou, V. C. Zoumpourlis, M. Takaoka, H. Nakagawa, F. Tort, K. Fugger, F. Johansson, M. Sehested, C. L. Andersen, L. Dyrskjot, T. Ørntoft, J. Lukas, C. Kittas, T. Helleday, T. D. Halazonetis, J. Bartek, V. G. Gorgoulis, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints. Nature 444, 633-637 (2006). [PubMed]

R. Di Micco, M. Fumagalli, A. Cicalese, S. Piccinin, P. Gasparini, C. Luise, C. Schurra, M. Garré, P. G. Nuciforo, A. Bensimon, R. Maestro, P. G. Pelicci, F. d’Adda di Fagagna, Oncogene-induced senescence is a DNA damage response triggered by DNA hyper-replication. Nature 444, 638-642 (2006). [PubMed]

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