A speculative model of the regulated binding and nuclear transport of the FA protein complex.

The FANCA and FANCG proteins bind initially in the cytoplasm of normal cells. Failure to bind results in the rapid degradation of both proteins. FANCG binds directly to the NLS region of the FANCA protein. In contrast, FANCC binding to the FANCA/FANCG complex is indirect and requires FANCA phosphorylation and the products of other FA genes. The FA protein complex subsequently translocates to the cell nucleus, where it executes a nuclear function, such as DNA repair or the segregation of sister chromatids, which helps maintain normal chromosome structure and stability. The FANCD protein may function downstream of the FA protein complex, as indicated. Patient-derived point mutations on the FANCA protein, such as the FANCA-H1110P and the FANCA-R1117G, block FANCA phosphorylation, FANCC binding, and nuclear translocation and retain the FANCG protein in the cytoplasm.