NF-kappa B is activated by several cellular stresses. Of these, the TNF alpha-induced activation pathway has been examined in detail. It was recently reported that receptor-interacting protein 1 (RIP1) is involved in DNA damage-induced NF-kappa B activation by forming a complex with the p53 interacting death domain protein (PIDD) and NF-kappa B essential modulator (NEMO) in the nucleus, although the underlying mechanism of this interaction has yet to be clarified. This study shows that siRNA knock-down of arrest-defective 1 protein (ARD1) abrogated doxorubicin- but not TNF alpha-induced activation. Conversely, the over-expression of ARD1 greatly enhanced NF-kappa B activation induced by doxorubicin. Immunoprecipitation experiments revealed that ARD1 interacted with RIP1 via the acetyltransferase domain. Furthermore, the over-expression of several domain-deleted ARD1 constructs demonstrated that the N-terminal and acetyltransferase domains of ARD1 were required for doxorubicin-induced NF-kappa B activation. Treatment of deacetylase inhibitor, trichostatin A, significantly increased doxorubicin-induced NF-kappa B activation in the presence of ARD1 but not acetyltransferase-defective ARD1 mutant. Moreover, N-terminal domain-deleted ARD1 could not be localized in the nucleus in response to doxorubicin treatment. These data indicate that the interaction between ARD1 and RIP1 plays an important role in the DNA damage-induced NF-kappa B activation, and that the acetyltransferase activity of ARD1 and its localization in to the nucleus are involved in such stress response. (C) 2012 Elsevier Inc. All rights reserved.