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

Oncogene volume 25, pages 6901–6914 (2006)Cite this article

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.

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Abbreviations

Hec1:

highly expressed in cancer 1

Zwint-1:

human ZW10 interacting protein

ZW10:

Zeste White 10

CIN:

Chromosome instability

M phase:

mitotic phase

Rb:

retinoblastoma protein

MT:

microtubule

kMT:

kinetochore microtubule

RNAi:

RNA interference

siRNA:

Short interfering RNA

Sc :

Saccharomyces cerevisiae

GFP:

Green fluorescent protein

GST:

glutathione S-tansferase

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Acknowledgements

We thank Dr Michael Goldberg for the human ZW10 cDNA plasmid, Dr Phang-Lang Chen and Bingnan Gu for technical support, Dr Daniel J Riley, Ms Saori Furuta and Lily Khidr for critically reading the manuscript. This work was supported by a grant from NIH (CA 107568) to WHL.

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Authors and Affiliations

  1. Department of Biological Chemistry, University of California, Irvine, CA, USA

    Y-T Lin, G Wu & W-H Lee

  2. Department of Molecular Medicine, University of Texas Health Science Center, San Antonio, TX, USA

    Y-T Lin & Y Chen

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Correspondence to W-H Lee.

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Lin, YT., Chen, Y., Wu, G. et al. Hec1 sequentially recruits Zwint-1 and ZW10 to kinetochores for faithful chromosome segregation and spindle checkpoint control. Oncogene 25, 6901–6914 (2006). https://doi.org/10.1038/sj.onc.1209687

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