Jennifer Rhodes,
Adam Amsterdam,
Takaomi Sanda,
Lisa A Moreau,
Keith McKenna,
Stefan Heinrichs,
Neil J Ganem,
Karen W Ho,
Donna S Neuberg,
Adam Johnston, [......],
Mark D Fleming,
Laura E MacConaill,
James F Amatruda,
Alejandro Gutierrez,
Ilene Galinsky,
Richard M Stone,
Eric A Ross, David S Pellman,
John P Kanki,
A Thomas Look
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ABSTRACT: 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.
Molecular and cellular biology 09/2009; 29(21):5911-22. · 6.06 Impact Factor
