| The human actin-binding protein filamin-1 (also known as ABP-280) participates in orthogonal actin networks, cellular stress response, signal transduction, cell migration and nuclear shuttling. BRCA2 is a tumor suppressor that plays significant roles in mammalian DNA damage response. Through a yeast two-hybrid system, an in vitro binding assay, and in vivo co-immunoprecipitations, I characterized an interaction between filamin-1 and BRCA2. The BRCA2-interacting domain of filamin-1 was mapped to its C terminus, and the filamin-1-interacting domain of BRCA2 was mapped to an internal conserved region of BRCA2. Although filamin-1 is known for its cytoplasmic functions in cell migration and signal transduction, I found that some filamin-1 resides in the nucleus. It is likely that filamin-1/BRCA2 interaction may serve to connect cytoskeleton networks to DNA damage response pathways.; I found that lack of filamin-1 renders a human melanoma cell line (M2) more sensitive to several genotoxic agents, including ionizing radiation, bleomycin and UV-C light. The ionizing radiation sensitivity of filamin-1 deficient cells was correlated with a delayed release from G2 arrest, which was regulated by Cyclin B/cdc2 phosphorylation. These data suggested a role of filamin-1 in cell cycle regulation in DNA damage response pathway. A few models are proposed regarding the potential pathways in which filamin-1 is involved in DNA damage response. |
