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J. Biol. Chem., Vol. 283, Issue 27, 18916-18925, July 4, 2008

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Septin 7 Interacts with Centromere-associated Protein E and Is Required for Its Kinetochore Localization^*

Mei Zhu, Fengsong Wang, Feng Yan, Phil Y. Yao, Jian Du, Xinjiao Gao, Xiwei Wang, Quan Wu, Tarsha Ward, Jingjing Li, Steve Kioko, Renming Hu^¶, Wei Xie^||, Xia Ding^**1, and Xuebiao Yao, American Digestive Health Foundation Industrial Research Scholar and a Georgia Cancer Coalition Eminent Cancer Research Scholar²

From the Division of Cellular Dynamics, Hefei National Laboratory for Physical Sciences at Microscale and the University of Science and Technology of China, Hefei 230027, China, the Cancer Biology Program, Morehouse School of Medicine, Atlanta, Georgia 30310, the ^¶Department of Endocrinology and Metabolism, Fudan University School of Medicine, Shanghai 200040, China, the ^||MOE Key Laboratory of Developmental Genes and Human Disease, Southeast University Medical School, Nanjing 210009, China, and the ^**Beijing University of Chinese Medicine, Beijing 100029, China

Chromosome segregation in mitosis is orchestrated by dynamic interaction between spindle microtubules and the kinetochore. Septin (SEPT) belongs to a conserved family of polymerizing GTPases localized to the metaphase spindle during mitosis. Previous study showed that SEPT2 depletion results in chromosome mis-segregation correlated with a loss of centromere-associated protein E (CENP-E) from the kinetochores of congressing chromosomes (1). However, it has remained elusive as to whether CENP-E physically interacts with SEPT and how this interaction orchestrates chromosome segregation in mitosis. Here we show that SEPT7 is required for a stable kinetochore localization of CENP-E in HeLa and MDCK cells. SEPT7 stabilizes the kinetochore association of CENP-E by directly interacting with its C-terminal domain. The region of SEPT7 binding to CENP-E was mapped to its C-terminal domain by glutathione S-transferase pull-down and yeast two-hybrid assays. Immunofluorescence study shows that SEPT7 filaments distribute along the mitotic spindle and terminate at the kinetochore marked by CENP-E. Remarkably, suppression of synthesis of SEPT7 by small interfering RNA abrogated the localization of CENP-E to the kinetochore and caused aberrant chromosome segregation. These mitotic defects and kinetochore localization of CENP-E can be successfully rescued by introducing exogenous GFP-SEPT7 into the SEPT7-depleted cells. These SEPT7-suppressed cells display reduced tension at kinetochores of bi-orientated chromosomes and activated mitotic spindle checkpoint marked by Mad2 and BubR1 labelings on these misaligned chromosomes. These findings reveal a key role for the SEPT7-CENP-E interaction in the distribution of CENP-E to the kinetochore and achieving chromosome alignment. We propose that SEPT7 forms a link between kinetochore distribution of CENP-E and the mitotic spindle checkpoint.

Received for publication, December 31, 2007 , and in revised form, April 14, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grants DK-56292, CA89019, and CA92080 (to X. Y.). This work was also supported by Chinese Project 973 Grants 2002CB713700, 2006CB943600, and 2007CB914503; Chinese Academy of Science Grants KSCX1-YW-R65 and KSCX2-YW-H-10; and Chinese Natural Science Foundation Grants 39925018, 30500183, 30121001, and 90508002 (to X. Y.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence may be addressed. E-mail: xiading6{at}yahoo.com. ² To whom correspondence may be addressed. Tel.: 86-551-3606304; Fax: 86-551-3606304; E-mail: yaoxb{at}ustc.edu.cn.

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