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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 ?H2AX (H2AX phosphorylated on Ser-139) by up-regulating N/E-cadherin and ?-catenin. ?-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.

SUBMITTER: Kang MA

PROVIDER: S-EPMC3351312 | biostudies-literature | 2012 May

REPOSITORIES: biostudies-literature

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Deregulation of DNA damage response pathway by intercellular contact.

Kang Meyke Ausman MA So Eui-Young EY Ouchi Toru T

The Journal of biological chemistry 20120319 20

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 cond ...[more]

PMID: 22431734

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