ZFIN ID: ZDB-PUB-070122-27
A mutation in separase causes genome instability and increased susceptibility to epithelial cancer
Shepard, J.L., Amatruda, J.F., Finkelstein, D., Ziai, J., Finley, K.R., Stern, H.M., Chiang, K., Hersey, C., Barut, B., Freeman, J.L., Lee, C., Glickman, J.N., Kutok, J.L., Aster, J.C., and Zon, L.I.
Date: 2007
Source: Genes & Development   21(1): 55-59 (Journal)
Registered Authors: Amatruda, James F., Barut, Bruce, Freeman, Jennifer, Hersey, Candace, Lee, Charles, Shepard, Jennifer, Stern, Howard, Ziai, James, Zon, Leonard I.
Keywords: Cancer, chromosome segregation, mitotic checkpoint, zebrafish
MeSH Terms:
  • Animals
  • Bromodeoxyuridine
  • Carcinoma, Pancreatic Ductal/etiology
  • Carcinoma, Pancreatic Ductal/pathology
  • Cell Cycle
  • Cell Cycle Proteins/genetics*
  • Disease Susceptibility*
  • Embryo, Nonmammalian/cytology
  • Embryo, Nonmammalian/metabolism
  • Endopeptidases/genetics*
  • Genomic Instability*
  • Heterozygote
  • Homozygote
  • Intestinal Neoplasms/etiology
  • Intestinal Neoplasms/pathology
  • Mitosis*
  • Mutation*
  • Neoplasms, Glandular and Epithelial/etiology*
  • Neoplasms, Glandular and Epithelial/pathology
  • Ploidies
  • Separase
  • Spindle Apparatus/genetics
  • Spindle Apparatus/pathology
  • Zebrafish/genetics
  • Zebrafish/growth & development
  • Zebrafish/metabolism
PubMed: 17210788 Full text @ Genes & Dev.
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.