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- Title
Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.
- Authors
Gorgoulis, Vassilis G.; Vassiliou, Leandros-Vassilios F.; Karakaidos, Panagiotis; Zacharatos, Panayotis; Kotsinas, Athanassios; Liloglou, Triantafillos; Venere, Monica; DiTullio, Richard A.; Kastrinakis, Nikolaos G.; Levy, Brynn; Kletsas, Dimitris; Yoneta, Akihiro; Herlyn, Meenhard; Kittas, Christos; Halazonetis, Thanos D.
- Abstract
DNA damage checkpoint genes, such as p53, are frequently mutated in human cancer, but the selective pressure for their inactivation remains elusive. We analysed a panel of human lung hyperplasias, all of which retained wild-type p53 genes and had no signs of gross chromosomal instability, and found signs of a DNA damage response, including histone H2AX and Chk2 phosphorylation, p53 accumulation, focal staining of p53 binding protein 1 (53BP1) and apoptosis. Progression to carcinoma was associated with p53 or 53BP1 inactivation and decreased apoptosis. A DNA damage response was also observed in dysplastic nevi and in human skin xenografts, in which hyperplasia was induced by overexpression of growth factors. Both lung and experimentally-induced skin hyperplasias showed allelic imbalance at loci that are prone to DNA double-strand break formation when DNA replication is compromised (common fragile sites). We propose that, from its earliest stages, cancer development is associated with DNA replication stress, which leads to DNA double-strand breaks, genomic instability and selective pressure for p53 mutations.
- Subjects
PRECANCEROUS conditions; DNA damage; ONCOGENES; CARCINOGENESIS; ONCOLOGY; BIOCHEMICAL genetics
- Publication
Nature, 2005, Vol 434, Issue 7035, p907
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature03485