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RESEARCH COMMUNICATION

A mutation in separase causes genome instability and increased susceptibility to epithelial cancer

¹ Children’s Hospital, Boston, Massachusetts 02115, USA; ² Department of Pathology, Brigham and Women’s Hospital, Boston, Massacusetts 02115, USA

Proper chromosome segregation is essential for maintenance of genomic integrity and instability resulting from failure of this process may contribute to cancer. Here, we demonstrate that a mutation in the mitotic regulator separase is responsible for the cell cycle defects seen in the zebrafish mutant, cease&desist (cds). Analysis of cds homozygous mutant embryos reveals high levels of polyploidy and aneuploidy, spindle defects, and a mitotic exit delay. Carcinogenesis studies demonstrated that cds heterozygous adults have a shift in tumor spectrum with an eightfold increase in the percentage of fish bearing epithelial tumors, indicating that separase is a tumor suppressor gene in vertebrates. These data strongly support a conserved cross-species role for mitotic checkpoint genes in genetic stability and epithelial carcinogenesis.

[Keywords: Cancer; chromosome segregation; mitotic checkpoint; zebrafish]

Received July 18, 2006; revised version accepted November 8, 2006.

⁴ Departments of Pediatrics and Molecular Biology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390, USA.

⁵ Corresponding author.

E-MAIL zon{at}enders.tch.harvard.edu; FAX (617) 730-0222.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1470407

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