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Molecular and Cellular Biology, November 2009, p. 5911-5922, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00558-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Emi1 Maintains Genomic Integrity during Zebrafish Embryogenesis and Cooperates with p53 in Tumor Suppression{triangledown}

Jennifer Rhodes,1* Adam Amsterdam,2 Takaomi Sanda,3 Lisa A. Moreau,3 Keith McKenna,3 Stefan Heinrichs,3 Neil J. Ganem,3 Karen W. Ho,3 Donna S. Neuberg,3 Adam Johnston,3 Yebin Ahn,3 Jeffery L. Kutok,4 Robert Hromas,5 Justin Wray,5 Charles Lee,4 Carly Murphy,4 Ina Radtke,6 James R. Downing,6 Mark D. Fleming,7 Laura E. MacConaill,3 James F. Amatruda,8 Alejandro Gutierrez,3 Ilene Galinsky,3 Richard M. Stone,3 Eric A. Ross,1 David S. Pellman,3 John P. Kanki,3 and A. Thomas Look3

Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111,1 Massachusetts Institute of Technology, Cambridge, Massachusetts 02139,2 Dana-Farber Cancer Institute, Boston, Massachusetts 02115,3 Brigham and Women's Hospital, Boston, Massachusetts 02115,4 University of New Mexico Cancer Center, Albuquerque, New Mexico 87131,5 St. Jude Children's Research Hospital, Memphis, Tennessee 38105,6 Children's Hospital, Boston, Massachusetts 02115,7 University of Texas Southwestern Medical Center, Dallas, Texas 753908

Received 29 April 2009/ Returned for modification 30 June 2009/ Accepted 13 August 2009

A growing body of evidence indicates that early mitotic inhibitor 1 (Emi1) is essential for genomic stability, but how this function relates to embryonic development and cancer pathogenesis remains unclear. We have identified a zebrafish mutant line in which deficient emi1 gene expression results in multilineage hematopoietic defects and widespread developmental defects that are p53 independent. Cell cycle analyses of Emi1-depleted zebrafish or human cells showed chromosomal rereplication, and metaphase preparations from mutant zebrafish embryos revealed rereplicated, unsegregated chromosomes and polyploidy. Furthermore, EMI1-depleted mammalian cells relied on topoisomerase II{alpha}-dependent mitotic decatenation to progress through metaphase. Interestingly, the loss of a single emi1 allele in the absence of p53 enhanced the susceptibility of adult fish to neural sheath tumorigenesis. Our results cast Emi1 as a critical regulator of genomic fidelity during embryogenesis and suggest that the factor may act as a tumor suppressor.

* Corresponding author. Mailing address: Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111. Phone: (215) 728-3829. Fax: (215) 728-2412. E-mail: Jennifer.Rhodes{at}fccc.edu

{triangledown} Published ahead of print on 24 August 2009.

Molecular and Cellular Biology, November 2009, p. 5911-5922, Vol. 29, No. 21
0270-7306/09/$08.00+0     doi:10.1128/MCB.00558-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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