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Filamin-A, also called actin-binding protein 280 (ABP-280), is predominantly a cytoplasmic protein.However, recent data suggest that a portion of this protein also resides in nucleus, and it interacts with the tumor suppressor BRCA2.The BRCA2 protein is a critical regulator of human RAD51 protein that is required for homologous recombinational DNA repair.We hypothesize that filamin-A plays an accessory role in supporting efficient homologous recombination repair, and regulate cell sensitivity to therapeutic DNA damages.To test this hypothesis, we used three pairs of cell lines with normal and reduced filamin-A expression, including breast cancer and melanoma cells.Down regulation of filamin-A reduced RAD51 nuclear focus formation and recruitment to chromatin in response to irradiation, and reduced homologous recombinational repair of DNA double strand breaks in an ISceI based recombination assay.Dominant negative fragments of filamin-A also inhibited homologous recombination.Furthermore, lack or reduction of filamin-A sensitizes cells to ionizing radiation, slows the removal of DNA damage induced *H2AX nuclear foci, as well as to chemotherapeutic drugs cisplatin and bleomycin.Tumor xenografts generated from filamin-A deficient ceils have significant better response to cisplatin treatment.These data illustrate the importance of the nuclear cytoskeleton structure in supporting the homologous recombinational DNA repair machinery, and further implicate a potential of filamin-A as a prognosis marker for DNA damage based cancer therapy.