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The central arbiter of cell fate in response to DNA damage is p53, which regulates the expression of genes involved in cell cycle arrest, survival and apoptosis. Although many responses initiated by DNA damage have been characterized, the role of actin cytoskeleton regulators is largely unknown. We now show that RhoC and LIM kinase 2 (LIMK2) are direct p53 target genes induced by genotoxic agents. Although RhoC and LIMK2 have well-established roles in actin cytoskeleton regulation, our results indicate that activation of LIMK2 also has a pro-survival function following DNA damage. LIMK inhibition by siRNA-mediated knockdown or selective pharmacological blockade sensitized cells to radio- or chemotherapy, such that treatments that were sub-lethal when administered singly resulted in cell death when combined with LIMK inhibition. Our findings suggest that combining LIMK inhibitors with genotoxic therapies could be more efficacious than single-agent administration, and highlight a novel connection between actin cytoskeleton regulators and DNA damage-induced cell survival mechanisms.

Original publication

DOI

10.1038/cr.2010.154

Type

Journal article

Journal

Cell Res

Publication Date

04/2011

Volume

21

Pages

666 - 682

Keywords

Actins, Animals, Antineoplastic Agents, Apoptosis, Cell Line, Tumor, Cell Survival, Chromatin Immunoprecipitation, Cytoskeleton, DNA Damage, Fluorescent Antibody Technique, Gene Expression Regulation, Gene Knockdown Techniques, Humans, Immunoblotting, Lim Kinases, Mice, Microarray Analysis, RNA, Small Interfering, Signal Transduction, Transcription, Genetic, Tumor Suppressor Protein p53, rho GTP-Binding Proteins, rho-Associated Kinases, rhoC GTP-Binding Protein