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J. Biol. Chem., Vol. 281, Issue 16, 11413-11421, April 21, 2006

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FAT10 Plays a Role in the Regulation of Chromosomal Stability^*

Jianwei Ren, Alison Kan, Siew Hong Leong, London L. P. J. Ooi^¶, Kuan-Teh Jeang^||, Samuel S. Chong^**, Oi Lian Kon, and Caroline G. L. Lee¹

From the Division of Medical Sciences and ^¶Department of Surgical Oncology, National Cancer Center, Singapore 169610, Singapore, the Departments of Biochemistry, ^**Pediatrics, and Obstetrics and Gynecology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117597, Singapore, the ^||Laboratory of Molecular Microbiology, NIAID, National Institutes of Health, Bethesda, Maryland 20892, and the Departments of Pediatrics and Gynecology and Obstetrics and the McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287

Aneuploidy is a key process in tumorigenesis. Dysfunction of the mitotic spindle checkpoint proteins has been implicated as a cause of aneuploidy in cells. We have previously reported that FAT10, a member of the ubiquitin-like modifier family of proteins, is overexpressed in several gastrointestinal and gynecological cancers. Here we show that FAT10 interacts with MAD2, a spindle checkpoint protein, during mitosis. Notably, we show that localization of MAD2 at the kinetochore during the prometaphase stage of the cell cycle was greatly reduced in FAT10-overexpressing cells. Furthermore, compared with parental HCT116 cells, fewer mitotic cells were observed after double thymidine-synchronized FAT10-overexpressing cells were released into nocodazole for more than 4 h. Nonetheless, when these double thymidine-treated cells were released into media, a similar number of G₁ parental and FAT10-overexpressing HCT116 cells was observed throughout the 10-h time course. Additionally, more nocodazole-treated FAT10-overexpressing cells escape mitotic controls and are multinucleate compared with parental cells. Significantly, we observed a higher degree of variability in chromosome number in cells overexpressing FAT10. Hence, our data suggest that high levels of FAT10 protein in cells lead to increased mitotic nondisjunction and chromosome instability, and this effect is mediated by an abbreviated mitotic phase and the reduction in the kinetochore localization of MAD2 during the prometaphase stage of the cell cycle.

Received for publication, July 5, 2005 , and in revised form, February 22, 2006.

^* This work was supported in part by grants from the BioMedical Research Council Singapore and the National Medical Research Council (to C. G. L. L.). 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 should be addressed: Division of Medical Sciences, National Cancer Center, Level 6, Lab 5, 11 Hospital Dr., Singapore 169610, Singapore. Tel.: 65-6436-8353; Fax: 65-6224-1778; E-mail: bchleec{at}nus.edu.sg.

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