Abstract
Chromosome alignment is required for accurate chromosome segregation. Chromosome misalignment can result in genomic instability and tumorigenesis. Here, we show that NF-κB activating protein (NKAP) is critical for chromosome alignment through anchoring CENP-E to kinetochores. NKAP knockdown causes chromosome misalignment and prometaphase arrest in human cells. NKAP dynamically localizes to kinetochores, and is required for CENP-E kinetochore localization. NKAP is SUMOylated predominantly in mitosis and the SUMOylation is needed for NKAP to bind CENP-E. A SUMOylation-deficient mutant of NKAP cannot support the localization of CENP-E on kinetochores or proper chromosome alignment. Moreover, Bub3 recruits NKAP to stabilize the binding of CENP-E to BubR1 at kinetochores. Importantly, loss of NKAP expression causes aneuploidy in cultured cells, and is observed in human soft tissue sarcomas. These findings indicate that NKAP is a novel and key regulator of mitosis, and its dysregulation might contribute to tumorigenesis by causing chromosomal instability.
Highlights
Chromosome alignment is required for accurate chromosome segregation
NF-kB activating protein (NKAP) undergoes SUMOylation in mitosis and SUMOylated NKAP is required for the recruitment of CENP-E to kinetochores
Since chromosome misalignment is frequently resulted from kinetochore– microtubule (KT–MT) attachment defects, we investigated whether KT–MT attachment was impaired in NKAP-knockdown cells
Summary
Chromosome alignment is required for accurate chromosome segregation. Chromosome misalignment can result in genomic instability and tumorigenesis. Loss of NKAP expression causes aneuploidy in cultured cells, and is observed in human soft tissue sarcomas These findings indicate that NKAP is a novel and key regulator of mitosis, and its dysregulation might contribute to tumorigenesis by causing chromosomal instability. Whereas some core components, such as the constitutive centromere-associated network (CCAN) proteins CENP-A and CENP-C, localize to the inner kinetochore throughout the cell cycle[4], many other proteins localize to the outer kinetochore transiently during mitosis[5,6] These proteins include kinetochore-bound motor proteins CENP-E and dynein, as well as the spindle assembly checkpoint (SAC) proteins, such as Bub[3], BubR1 and Mad[2] (refs 5,7). Loss of NKAP causes chromosome missegregation and aneuploidy and is observed in human soft tissue sarcomas
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