An oncogene-induced DNA damage model for cancer development.
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.
Halazonetis
Thanos D
TD
Department of Molecular Biology and Department of Biochemistry, University of Geneva, CH-1205 Geneva, Switzerland. Thanos.Halazonetis@molbio.unige.ch
Gorgoulis
Vassilis G
VG
Bartek
Jiri
J
D049109:Cell Proliferation; D053903:DNA Breaks, Double-Stranded; D004249:DNA Damage; D004261:DNA Replication; D018450:Disease Progression; D016158:Genes, p53; D042822:Genomic Instability; D006801:Humans; D008954:Models, Biological; D009154:Mutation; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D009857:Oncogenes; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016159:Tumor Suppressor Protein p53