Abstract
The Fanconi anemia (FA) proteins are involved in a signaling network that assures the safeguard of chromosomes. To understand the function of FA proteins in cellular division events, we investigated the interaction between Stathmin-1 (STMN1) and the FA group C (FANCC) protein. STMN1 is a ubiquitous cytosolic protein that regulates microtubule dynamics. STMN1 activities are regulated through phosphorylation-dephosphorylation mechanisms that control assembly of the mitotic spindle, and dysregulation of STMN1 phosphorylation is associated with mitotic aberrancies leading to chromosome instability and cancer progression. Using different biochemical approaches, we showed that FANCC interacts and co-localizes with STMN1 at centrosomes during mitosis. We also showed that FANCC is required for STMN1 phosphorylation, as mutations in FANCC reduced serine 16- and 38-phosphorylated forms of STMN1. Phosphorylation of STMN1 at serine 16 is likely an event dependent on a functional FA pathway, as it is reduced in FANCA- and FANCD2-mutant cells. Furthermore, FA-mutant cells exhibited mitotic spindle anomalies such as supernumerary centrosomes and shorter mitotic spindles. These results suggest that FA proteins participate in the regulation of cellular division via the microtubule-associated protein STMN1.
Highlights
Fanconi anemia (FA) is a rare genetic disorder associated with a progressive failure of the hematopoietic system, generally manifested as anemia, thrombopenia or pancytopenia [1]
FANCC was shown to form a complex with the mitotic cyclin-dependent kinase 1 (CDK1), a kinase located at centrosomes and implicated in the initiation of mitosis [21]
These findings indicate that FANCC N- and C-terminal domains effectuate the interaction with both STMN family members, STMN1 and STMN2
Summary
Fanconi anemia (FA) is a rare genetic disorder associated with a progressive failure of the hematopoietic system, generally manifested as anemia, thrombopenia or pancytopenia [1]. FA patients are prone to non-hematological malignancies including squamous cell carcinomas [2]. Eighteen genes have been associated with FA, and their products are thought to function through a signaling network in response to DNA crosslink damage [3,4,5,6]. FA proteins can be divided into three protein complexes that include a multi-protein core complex (FANCA, FANCB, FANCC, FANCE, FANCF, FANCG and FANCL), a two-protein substrate (FANCD2 and FANCI) and downstream effectors (FANCD1, FANCJ, FANCM, FANCN, FANCO, FANCP, FANCQ, FANCS) [7,8,9].
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