The fanconi anemia c protein regulates cellular division via the microtubule-associated protein stathmin-1

Fanconi Anemia (FA) belongs to the inherited bone marrow failure syndromes characterized by a progressive decline in primitive hematopoietic cells due to accelerated cycling and hypersensitivity to various external cellular cues. These cellular defects favour the development of clonal proliferation and leads to leukemia. Proteins mutated in FA have been implicated in mitotic events assuring the safeguard of chromosome segregation. Consequently, defective FA proteins have been associated with a higher rate of cytokinesis failure, aneuploidy and chromosome missegregation, which are hallmarks of cancer cells. In an attempt to identify FA protein's function in cellular division events, we identified through Yeasts-2-Hybrid screening approaches, the microtubule-associated protein Stathmin (STMN), as a binding partner of the FA protein C (FANCC). Through different biochemical approaches, we confirmed the FANCC-STMN interaction. FA-disease causing mutations in FANCC prevent its interaction with STMN. We observed that FANCC with Phospho-STMN co-localizes to centrosomes during mitosis. In addition, we found that FANCC modulates STMN phosphorylation status on serine 16 and 38 during cellular division. The phosphorylation status of STMN during the cell cycle requires a functional FANCC. These results suggest that FANCC participates in the regulation of cellular division via the microtubule-associated protein STMN. Previous studies have shown that elevated levels of STMN are found in many cancers including leukemia whereas a dramatic decrease in STMN levels is found in hematopoietic cells upon differentiation along different lineages. Consequently, we propose that misregulation of STMN1 activity combined with the DNA repair defects in FA cells may account for the loss of hematopoietic stem cells and increase in cancer susceptibility seen in patients with FA.