Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Vassilis G Gorgoulis; Leandros-Vassilios F Vassiliou; Panagiotis Karakaidos; Panayotis Zacharatos; Athanassios Kotsinas; Triantafillos Liloglou; Monica Venere; Richard A Ditullio Jr; Nikolaos G Kastrinakis; Brynn Levy; Dimitris Kletsas; Akihiro Yoneta; Meenhard Herlyn; Christos Kittas; Thanos D Halazonetis

doi:10.1038/nature03485

Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions

Nature. 2005 Apr 14;434(7035):907-13. doi: 10.1038/nature03485.

Authors

Vassilis G Gorgoulis¹, Leandros-Vassilios F Vassiliou, Panagiotis Karakaidos, Panayotis Zacharatos, Athanassios Kotsinas, Triantafillos Liloglou, Monica Venere, Richard A Ditullio Jr, Nikolaos G Kastrinakis, Brynn Levy, Dimitris Kletsas, Akihiro Yoneta, Meenhard Herlyn, Christos Kittas, Thanos D Halazonetis

Affiliation

¹ Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.

PMID: 15829965
DOI: 10.1038/nature03485

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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

MeSH terms

Allelic Imbalance / genetics
Apoptosis
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Checkpoint Kinase 2
Chromosome Fragility
DNA Damage* / genetics
DNA Replication
Disease Progression
Enzyme Activation
Genes, p53 / genetics
Genomic Instability / genetics*
Histones / metabolism
Humans
Hyperplasia / enzymology
Hyperplasia / genetics
Hyperplasia / metabolism
Hyperplasia / pathology
Intracellular Signaling Peptides and Proteins / metabolism
Mutation / genetics
Phosphoproteins / metabolism
Phosphorylation
Precancerous Conditions / enzymology
Precancerous Conditions / genetics
Precancerous Conditions / pathology*
Precancerous Conditions / prevention & control*
Protein Serine-Threonine Kinases / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism
Tumor Suppressor p53-Binding Protein 1

Substances

Histones
Intracellular Signaling Peptides and Proteins
Phosphoproteins
TP53BP1 protein, human
Tumor Suppressor Protein p53
Tumor Suppressor p53-Binding Protein 1
Checkpoint Kinase 2
CHEK2 protein, human
Protein Serine-Threonine Kinases