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Papers In Press, published online ahead of print February 22, 2006
Biochemistry Dept., National University of Singapore, Singapore, Singapore 117597
Corresponding Author: bchleec{at}nus.edu.sg
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 over-expressed 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 over-expressing cells. Furthermore, compared to parental HCT116 cells, fewer mitotic cells were observed after double-thymidine synchronized FAT10 over-expressing cells were released into nocodazole for more than four hours. Nonetheless, when these double-thymidine treated cells were released into media, similar number of G1 parental and FAT10 over-expressing HCT116 cells were observed throughout the ten hour time-course. Additionally, more nocodazole-treated FAT10 over-expressing cells escape mitotic controls and are multi-nucleate compared to parental cells. Significantly, we observed a higher degree of variability in chromosome number in cells over-expressing FAT10. Hence, our data suggest that high levels of FAT10 protein in cells leads to increased mitotic non-dysjunction 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.
J. Biol. Chem, 10.1074/jbc.M507218200
Submitted on July 5, 2005
Revised on February 22, 2006
Accepted on February 22, 2006
Fat10 plays a role in the regulation of chromosomal stability
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