Intercellular contact determines cellular resistance to radiation and chemotherapeutic agents by regulating basal levels of histone H2AX

Accurate execution of the DNA Damage Response (DDR) pathway is not only crucial for genomic stability and cellular defense against malignant progression, but it also determines cancer cells' sensitivity to cell death induced by ionizing radiation and chemotherapeutic agents. One of the key players in the DDR cascade is histone H2AX. H2AX not only indicates the localization of DNA DSBs, but it also promotes the accumulation of DNA repair factors at DSB sites and determines between life and death after DNA damage. While the role of H2AX in the DDR has been thoroughly investigated, little is known about its function and regulation under physiological conditions.;In this thesis, we delineate the mechanism of H2AX regulation by intercellular contact in the absence of DNA damage and describe novel functions of the protein. We found that increased intercellular contact stabilizes histone H2AX and gamma-H2AX (H2AX S139P) by decreasing RNF8-mediated downregulation of H2AX, which in turn is accomplished through N/E-cadherin/gamma-catenin/Lef-1-mediated suppression of RNF8 expression. Through stabilized H2AX, intercellular contact creates a state of DDR hyperphosphorylation, increases basal cell death by increasing Nox1-mediated ROS production and JNK activation, and induces resistance to DSB-induced cell death, possibly through the positive selection of cells with defects in p53-mediated apoptosis. Together, our results suggest that intercellular contact might induce malignant transformation or resistance to anticancer treatments through H2AX-mediated deregulation of the DDR and cell death pathways.