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Oncogene. 2006 Nov 2;25(52):6901-14. Epub 2006 May 29.

Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control.

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  • 1Department of Biological Chemistry, University of California, Irvine, CA 92697-4037, USA.

Abstract

Faithful chromosome segregation is essential for maintaining the genomic integrity, which requires coordination among chromosomes, kinetochores, centrosomes and spindles during mitosis. Previously, we discovered a novel coiled-coil protein, highly expressed in cancer 1 (Hec1), which is indispensable for this process. However, the precise underlying mechanism remains unclear. Here, we show that Hec1 directly interacts with human ZW10 interacting protein (Zwint-1), a binding partner of Zeste White 10 (ZW10) that is required for chromosome motility and spindle checkpoint control. In mitotic cells, Hec1 transiently forms complexes with Zwint-1 and ZW10 in a temporal and spatial manner. Although the three proteins have variable cell cycle-dependent expression profiles, they can only be co-immunoprecipitated during M phase. Immunofluorescent study showed that Hec1 and Zwint-1 co-localize at kinetochores beginning at prophase and that ZW10 joins them later at prometaphase. Depletion of Hec1 impairs the recruitment of both Zwint-1 and ZW10 to kinetochores, while depletion of Zwint-1 abrogates the kinetochore localization of ZW10 but not Hec1. The results suggest that the localization of Hec1 at kinetochores is required for the sequential recruitment of Zwint-1 and ZW10. Disrupting this recruitment by inhibiting the expression of Hec1 or Zwint-1 causes chromosome missegregation, spindle checkpoint failure, and eventually cell death upon cytokinesis. Taken together, these results, at least in part, provide a molecular basis to explain how Hec1 plays a crucial role for spindle checkpoint control and faithful chromosome segregation.

PMID:
16732327
[PubMed - indexed for MEDLINE]
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