Human α spectrin II and the Fanconi anemia proteins FANCA and FANCC interact to form a nuclear complex

Fanconi anemia (FA) is a genetic disorder characterized by bone marrow failure, congenital abnormalities, cancer susceptibility, and a marked cellular hypersensitivity to DNA interstrand cross-linking agents, which correlates with a defect in ability to repair this type of damage, We have previously identified an approximately 230-kDa protein present, in a nuclear protein complex in normal human lymphoblastoid cells that is involved in repair of DNA interstrand cross-links and shows reduced levels in FA-A cell nuclei. The FANCA gene appears to play a role in the stability or expression of this protein. me now show that p230 is a well known structural protein, human ct spectrin II (alpha SpII Sigma*), and that levels of alpha SpII Sigma* are not only significantly reduced in FA-A cells but also in FA-B, FA-C and FA-D cells (i.e. in all FA cell Lines tested), suggesting a role for these FA proteins in the stability or expression of alpha SpII Sigma*. These studies also show that alpha SpII Sigma* forms a complex in the nucleus with the FANCA and FANCC proteins. alpha SpII Sigma* may thus act as a scaffold to align or enhance interactions between FA proteins and proteins involved in DNA repair. These results suggest that FA represents a disorder in which there is a deficiency in alpha SpII Sigma*.