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The Membrane-associated Form of the DNA Repair Protein Ku is Involved in Cell Adhesion to Fibronectin

Abstract : The Ku heterodimer (Ku70/Ku80) plays a central role in DNA double-strand breaks recognition and repair. However, Ku is expressed also on the surface of different types of cells along with its intracellular pool within the nucleus and the cytoplasm. Participation of membrane-associated Ku in cell-cell interaction has been reported recently. Here, we describe a novel function of cell-surface Ku as an adhesion receptor for fibronectin (Fn). The role of Ku in cell adhesion was investigated by comparing the Ku80 deficient Chinese hamster ovary (CHO) cell line, xrs-6, with clones transfected stably with either the hamster or human Ku80 cDNA. Ku expression in transfectant cells resulted in a significant increased adhesion on Fn and type IV collagen as compared to control cells. The observed increase in cell adhesion relied on Ku cell-surface expression, since antibodies directed against Ku70 or Ku80 subunit inhibited adhesion on Fn of Ku80, but not control vector, transfected xrs-6 cells. In addition, both Ku70 and Ku80 present a structural relationship with integrin I (or A) domains and the A1 and A3 domains of von Willebrand factor, domains known to be involved in Fn binding. Both Ku70 and Ku80 exhibit a complete set of residues compatible in their position and chemical nature with the formation of a metal ion-dependent adhesion (MIDAS) site implicated in ligand binding and integrin activation. Taken together, these functional and structural approaches support a new role for Ku as an adhesion receptor for Fn. Ku is a complex composed of two tightly associated subunits called Ku70 and Ku80. 1 Ku is the DNA-binding component of the DNA-dependent kinase (DNA-PK) complex. Ku binds to DNA double strand breaks (DSBs), recruits and activates the large catalytic subunit of DNA-PK, a member of the phosphatidylinositol 3-kinase superfamily. 2 As a major component of the non-homologous end-joining (NHEJ) pathway, the entire DNA-PK complex is required for the repair of DSBs and the rejoining of the DNA ends specifically generated during V(D)J recombination. 3 Ku was originally reported to be a nuclear protein, consistent with its function in DNA DSBs repair. On the other hand, several studies have revealed the cyto-plasmic and the cell-surface localization of Ku proteins in a variety of tumor cells, including leukemia, multiple myeloma and solid tumor cell lines. 4-9 Furthermore, a recent work demonstrates the localization of the whole DNA-PK complex in membrane lipid rafts of mammalian cells. 10 These recent results suggest that the extra-nuclear localiz-ation of DNA-PK complex is serving additional role besides its main function in DNA DSBs repair. Indeed, the participation of Ku70 and Ku80 in cell-cell interaction has been described recently. 6,8,9 Both Ku80 and Ku70 are up-regulated 0022-2836/$-see front matter q
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Sylvie Monferran, Catherine Muller, Lionel Mourey, Philippe Frit, Bernard Salles. The Membrane-associated Form of the DNA Repair Protein Ku is Involved in Cell Adhesion to Fibronectin. Journal of Molecular Biology, Elsevier, 2004, 337, pp.503 - 511. ⟨10.1016/j.jmb.2004.01.057⟩. ⟨hal-03004153⟩

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