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

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

Research output: Contribution to journalArticle

76 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)55-59
Number of pages5
JournalGenes and Development
Volume21
Issue number1
DOIs
StatePublished - Jan 1 2007

Fingerprint

Separase
Genomic Instability
Mutation
Carcinogenesis
M Phase Cell Cycle Checkpoints
Neoplasms
Chromosome Segregation
Polyploidy
Aneuploidy
Zebrafish
Tumor Suppressor Genes
Vertebrates
Cell Cycle
Fishes
Embryonic Structures
Maintenance
Genes

Keywords

  • Cancer
  • Chromosome segregation
  • Mitotic checkpoint
  • Zebrafish

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

Cite this

A mutation in separase causes genome instability and increased susceptibility to epithelial cancer. / Shepard, Jennifer L.; Amatruda, James F.; Finkelstein, David; Ziai, James; Finley, K. Rose; Stern, Howard M.; Chiang, Ken; Hersey, Candace; Barut, Bruce; Freeman, Jennifer L.; Lee, Charles; Glickman, Jonathan N.; Kutok, Jeffery L.; Aster, Jon C.; Zon, Leonard I.

In: Genes and Development, Vol. 21, No. 1, 01.01.2007, p. 55-59.

Research output: Contribution to journalArticle

Shepard, JL, Amatruda, JF, Finkelstein, D, Ziai, J, Finley, KR, Stern, HM, Chiang, K, Hersey, C, Barut, B, Freeman, JL, Lee, C, Glickman, JN, Kutok, JL, Aster, JC & Zon, LI 2007, 'A mutation in separase causes genome instability and increased susceptibility to epithelial cancer', Genes and Development, vol. 21, no. 1, pp. 55-59. https://doi.org/10.1101/gad.1470407
Shepard, Jennifer L. ; Amatruda, James F. ; Finkelstein, David ; Ziai, James ; Finley, K. Rose ; Stern, Howard M. ; Chiang, Ken ; Hersey, Candace ; Barut, Bruce ; Freeman, Jennifer L. ; Lee, Charles ; Glickman, Jonathan N. ; Kutok, Jeffery L. ; Aster, Jon C. ; Zon, Leonard I. / A mutation in separase causes genome instability and increased susceptibility to epithelial cancer. In: Genes and Development. 2007 ; Vol. 21, No. 1. pp. 55-59.
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