Fhit deficiency-induced global genome instability promotes mutation and clonal expansion

Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome 'caretaker' whose loss initiates genome instability in preneoplastic lesions. We have...

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Bibliographic Details
Published in:PloS one 2013-11, Vol.8 (11), p.e80730
Main Authors: Miuma, Satoshi, Saldivar, Joshua C, Karras, Jenna R, Waters, Catherine E, Paisie, Carolyn A, Wang, Yao, Jin, Victor, Sun, Jin, Druck, Teresa, Zhang, Jie, Huebner, Kay
Format: Article
Language:English
Subjects:
9,10-Dimethyl-1,2-benzanthracene
Acid Anhydride Hydrolases - deficiency
Acid Anhydride Hydrolases - genetics
Acid Anhydride Hydrolases - metabolism
Alleles
Alterations
Analysis
Animals
Anthracene
Apoptosis
Cancer
Carcinogens
Caspase
Caspase 3 - metabolism
Caspase-3
Cell culture
Cell cycle
Cell Line
Cell proliferation
Copy number
Deoxyribonucleic acid
DNA
DNA damage
DNA repair
Embryo fibroblasts
Embryos
Experiments
Fibroblasts
Fibroblasts - metabolism
Gene expression
Gene mutation
Gene therapy
Genes
Genetic aspects
Genetics
Genomes
Genomic instability
Genomic Instability - genetics
Genomic Instability - physiology
Genomics
Immunology
Informatics
Instability
Kidney - metabolism
Kidneys
Laboratory animals
Lesions
Liver
Loss of Heterozygosity
Mcl-1 protein
Mice
Mutation
Myeloid Cell Leukemia Sequence 1 Protein - metabolism
Neoplasm Proteins - deficiency
Neoplasm Proteins - genetics
Neoplasm Proteins - metabolism
p53 Protein
Phenotypes
Proteins
rho GTP-Binding Proteins - metabolism
Rodents
Senescence
Stability
Tissue culture
Tumor proteins
Tumor Suppressor Protein p53 - metabolism
Tumors
Virology
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Summary:Loss of Fhit expression, encoded at chromosome fragile site FRA3B, leads to increased replication stress, genome instability and accumulation of genetic alterations. We have proposed that Fhit is a genome 'caretaker' whose loss initiates genome instability in preneoplastic lesions. We have characterized allele copy number alterations and expression changes observed in Fhit-deficient cells in conjunction with alterations in cellular proliferation and exome mutations, using cells from mouse embryo fibroblasts (MEFs), mouse kidney, early and late after establishment in culture, and in response to carcinogen treatment. Fhit (-/-) MEFs escape senescence to become immortal more rapidly than Fhit (+/+) MEFs; -/- MEFs and kidney cultures show allele losses and gains, while +/+ derived cells show few genomic alterations. Striking alterations in expression of p53, p21, Mcl1 and active caspase 3 occurred in mouse kidney -/- cells during progressive tissue culture passage. To define genomic changes associated with preneoplastic changes in vivo, exome DNAs were sequenced for +/+ and -/- liver tissue after treatment of mice with the carcinogen, 7,12-dimethylbenz[a]anthracene, and for +/+ and -/- kidney cells treated in vitro with this carcinogen. The -/- exome DNAs, in comparison with +/+ DNA, showed small insertions, deletions and point mutations in more genes, some likely related to preneoplastic changes. Thus, Fhit loss provides a 'mutator' phenotype, a cellular environment in which mild genome instability permits clonal expansion, through proliferative advantage and escape from apoptosis, in response to pressures to survive.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0080730