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Vol. 19, Issue 2, 587-594, February 2008

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KNL1 and the CENP-H/I/K Complex Coordinately Direct Kinetochore Assembly in Vertebrates

Iain M. Cheeseman^*,, Tetsuya Hori, Tatsuo Fukagawa, and Arshad Desai^*

*Ludwig Institute for Cancer Research, and Department of Cellular and Molecular Medicine, University of California San Diego, La Jolla, CA 92093; and Department of Molecular Genetics, National Institute of Genetics and The Graduate University for Advanced Studies, Mishima, Shizuoka 411-8540, Japan

Submitted October 19, 2007; Revised November 8, 2007; Accepted November 20, 2007
Monitoring Editor: Kerry Bloom

Chromosome segregation during mitosis requires the assembly of a large proteinaceous structure termed the kinetochore. In Caenorhabditis elegans, KNL-1 is required to target multiple outer kinetochore proteins. Here, we demonstrate that the vertebrate KNL1 counterpart is essential for chromosome segregation and is required to localize a subset of outer kinetochore proteins. However, unlike in C. elegans, depletion of vertebrate KNL1 does not abolish kinetochore localization of the microtubule-binding Ndc80 complex. Instead, we show that KNL1 and CENP-K, a subunit of a constitutively centromere-associated complex that is missing from C. elegans, coordinately direct Ndc80 complex localization. Simultaneously reducing both hKNL1 and CENP-K function abolishes all aspects of kinetochore assembly downstream of centromeric chromatin and causes catastrophic chromosome segregation defects. These findings explain discrepancies in kinetochore assembly pathways between different organisms and reveal a surprising plasticity in the assembly mechanism of an essential cell division organelle.

Present address: Whitehead Institute for Biomedical Research, and Department of Biology, Massachusetts Institute of Technology, Suite 401, Nine Cambridge Center, Cambridge, MA 02142.

Address correspondence to: Arshad Desai (abdesai{at}ucsd.edu) or Iain Cheeseman (icheese{at}wi.mit.edu)