title: Deregulation of DNA damage response pathway by intercellular contact.
abstract: Deregulation of the DNA damage response (DDR) pathway could compromise genomic integrity in normal cells and reduce cancer cell sensitivity to anticancer treatments. We found that intercellular contact stabilizes histone H2AX and γH2AX (H2AX phosphorylated on Ser-139) by up-regulating N/E-cadherin and γ-catenin. γ-catenin and its DNA-binding partner LEF-1 indirectly increase levels of H2AX by suppressing the promoter of the RNF8 ubiquitin ligase, which decreases levels of H2AX protein under conditions of low intercellular contact. Hyperphosphorylation of DDR proteins is induced by up-regulated H2AX. Constitutive apoptosis is caused in confluent cells but is not further induced by DNA damage. This is conceivably due to insufficient p53 activation because ChIP assay shows that its DNA binding ability is not induced in those cells. Together, our results illustrate a novel mechanism of the regulation of DDR proteins by the cadherin-catenin pathway.
authors.affiliation: Department of Molecular Biosciences, Interdepartmental Biological Sciences Program, Northwestern University, Evanston, Illinois 60201, USA.
authors.forename: Meyke Ausman
authors.initials: MA
authors.lastname: Kang
authors.forename: Eui-Young
authors.initials: EY
authors.lastname: So
authors.forename: Toru
authors.initials: T
authors.lastname: Ouchi
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D004249:DNA Damage / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D051180:Desmoplakins / Q000235:genetics / Q000378:metabolism; D006367:HeLa Cells; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007365:Intercellular Junctions / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010766:Phosphorylation / Q000502:physiology; D055550:Protein Stability; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism; D051185:gamma Catenin
chemical_list: D015820:Cadherins; D004268:DNA-Binding Proteins; D051180:Desmoplakins; D006657:Histones; C495292:JUP protein, human; C486521:RNF8 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051185:gamma Catenin; C549817:Rnf8 protein, mouse; D044767:Ubiquitin-Protein Ligases