Interaction with BRCA2 suggests a role for filamin-1 (hsFLNa) in DNA damage response.

The BRCA2 tumor suppressor plays significant roles in DNA damage response. The human actin binding protein filamin-1 (hsFLNa, also known as ABP-280) participates in orthogonal actin network, cellular stress responses, signal transduction, and cell migration. Through a yeast two-hybrid system, an in vitro binding assay, and in vivo co-immunoprecipitations, we identified an interaction between BRCA2 and hsFLNa. The hsFLNa binding domain of BRCA2 was mapped to an internal conserved region, and the BRCA2-interacting domain of hsFLNa was mapped to its C terminus. Although hsFLNa is known for its cytoplasmic functions in cell migration and signal transduction, some hsFLNa resides in the nucleus, raising the possibility that it participates in DNA damage response through a nuclear interaction with BRCA2. Lack of hsFLNa renders a human melanoma cell line (M2) more sensitive to several genotoxic agents including gamma irradiation, bleomycin, and ultraviolet-c light. These results suggest that BRCA2/hsFLNa interaction may serve to connect cytoskeletal signal transduction to DNA damage response pathways.