A mutation in separase causes genome instability and increased susceptibility to epithelial cancer.
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.
Shepard
Jennifer L
JL
Children's Hospital, Boston, Massachusetts 02115, USA.
Amatruda
James F
JF
Finkelstein
David
D
Ziai
James
J
Finley
K Rose
KR
Stern
Howard M
HM
Chiang
Ken
K
Hersey
Candace
C
Barut
Bruce
B
Freeman
Jennifer L
JL
Lee
Charles
C
Glickman
Jonathan N
JN
Kutok
Jeffery L
JL
Aster
Jon C
JC
Zon
Leonard I
LI
D000818:Animals; D001973:Bromodeoxyuridine; D021441:Carcinoma, Pancreatic Ductal / Q000209:etiology / Q000473:pathology; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics*; D004198:Disease Susceptibility; D004625:Embryo, Nonmammalian / Q000166:cytology / Q000378:metabolism; D010450:Endopeptidases / Q000235:genetics*; D042822:Genomic Instability; D006579:Heterozygote; D006720:Homozygote; D007414:Intestinal Neoplasms / Q000209:etiology / Q000473:pathology; D008938:Mitosis; D009154:Mutation; D009375:Neoplasms, Glandular and Epithelial / Q000209:etiology* / Q000473:pathology; D011003:Ploidies; D064247:Separase; D008941:Spindle Apparatus / Q000235:genetics / Q000473:pathology; D015027:Zebrafish / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
D018797:Cell Cycle Proteins; D010450:Endopeptidases; D064247:Separase; D001973:Bromodeoxyuridine