Activation of the DNA damage checkpoint and genomic instability in human precancerous lesions.
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.
Gorgoulis
Vassilis G
VG
Department of Histology and Embryology, School of Medicine, University of Athens, Athens GR-11527, Greece.
Vassiliou
Leandros-Vassilios F
LV
Karakaidos
Panagiotis
P
Zacharatos
Panayotis
P
Kotsinas
Athanassios
A
Liloglou
Triantafillos
T
Venere
Monica
M
Ditullio
Richard A
RA
Kastrinakis
Nikolaos G
NG
Levy
Brynn
B
Kletsas
Dimitris
D
Yoneta
Akihiro
A
Herlyn
Meenhard
M
Kittas
Christos
C
Halazonetis
Thanos D
TD
D022981:Allelic Imbalance / Q000235:genetics; D017209:Apoptosis; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D064447:Checkpoint Kinase 2; D002873:Chromosome Fragility; D004249:DNA Damage / Q000235:genetics; D004261:DNA Replication; D018450:Disease Progression; D004789:Enzyme Activation; D016158:Genes, p53 / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics*; D006657:Histones / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia / Q000201:enzymology / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D009154:Mutation / Q000235:genetics; D010750:Phosphoproteins / Q000378:metabolism; D010766:Phosphorylation; D011230:Precancerous Conditions / Q000201:enzymology / Q000235:genetics / Q000473:pathology* / Q000517:prevention & control*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D000071857:Tumor Suppressor p53-Binding Protein 1
D006657:Histones; D047908:Intracellular Signaling Peptides and Proteins; D010750:Phosphoproteins; C498301:TP53BP1 protein, human; D016159:Tumor Suppressor Protein p53; D000071857:Tumor Suppressor p53-Binding Protein 1; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases