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Science 7 March 2008:
Vol. 319. no. 5868, pp. 1352 - 1355
DOI: 10.1126/science.1140735
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Review

An Oncogene-Induced DNA Damage Model for Cancer Development

Thanos D. Halazonetis,1* Vassilis G. Gorgoulis,2 Jiri Bartek3

Of all types of DNA damage, DNA double-strand breaks (DSBs) pose the greatest challenge to cells. One might have, therefore, anticipated that a sizable number of DNA DSBs would be incompatible with cell proliferation. Yet recent experimental findings suggest that, in both precancerous lesions and cancers, activated oncogenes induce stalling and collapse of DNA replication forks, which in turn leads to formation of DNA DSBs. This continuous formation of DNA DSBs may contribute to the genomic instability that characterizes the vast majority of human cancers. In addition, in precancerous lesions, these DNA DSBs activate p53, which, by inducing apoptosis or senescence, raises a barrier to tumor progression. Breach of this barrier by various mechanisms, most notably by p53 mutations, that impair the DNA damage response pathway allows cancers to develop. Thus, oncogene-induced DNA damage may explain two key features of cancer: genomic instability and the high frequency of p53 mutations.

1 Department of Molecular Biology and Department of Biochemistry, University of Geneva, CH-1205 Geneva, Switzerland.
2 Department of Histology and Embryology, School of Medicine, University of Athens, GR-11527 Athens, Greece.
3 Institute of Cancer Biology and Centre for Genotoxic Stress Research, Danish Cancer Society, DK-2100 Copenhagen, Denmark.

* To whom correspondence should be addressed. E-mail: Thanos.Halazonetis{at}molbio.unige.ch

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