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

Abstract

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.

• Authors: Jennifer L Shepard, James F Amatruda, David Finkelstein, James Ziai, K Rose Finley, Howard M Stern, Ken Chiang, Candace Hersey, Bruce Barut, Jennifer L Freeman, Charles Lee, Jonathan N Glickman, Jeffery L Kutok, Jon C Aster, Leonard I Zon
• Journal: Genes & development (Genes Dev) Vol. 21 Issue 1 Pg. 55-9 (Jan 01 2007) ISSN: 0890-9369 [Print] United States
• PMID: 17210788 (Publication Type: Journal Article)

Chemical References

• Cell Cycle Proteins
• Endopeptidases
• Separase
• Bromodeoxyuridine

Topics

• Animals
• Bromodeoxyuridine
• Carcinoma, Pancreatic Ductal (etiology, pathology)
• Cell Cycle
• Cell Cycle Proteins (genetics)
• Disease Susceptibility
• Embryo, Nonmammalian (cytology, metabolism)
• Endopeptidases (genetics)
• Genomic Instability
• Heterozygote
• Homozygote
• Intestinal Neoplasms (etiology, pathology)
• Mitosis
• Mutation
• Neoplasms, Glandular and Epithelial (etiology, pathology)
• Ploidies
• Separase
• Spindle Apparatus (genetics, pathology)
• Zebrafish (genetics, growth & development, metabolism)