Emi1 maintains genomic integrity during zebrafish embryogenesis and cooperates with p53 in tumor suppression.
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.
Rhodes
Jennifer
J
Fox Chase Cancer Center, 333 Cottman Ave., Philadelphia, PA 19111, USA. Jennifer.Rhodes@fccc.edu
Amsterdam
Adam
A
Sanda
Takaomi
T
Moreau
Lisa A
LA
McKenna
Keith
K
Heinrichs
Stefan
S
Ganem
Neil J
NJ
Ho
Karen W
KW
Neuberg
Donna S
DS
Johnston
Adam
A
Ahn
Yebin
Y
Kutok
Jeffery L
JL
Hromas
Robert
R
Wray
Justin
J
Lee
Charles
C
Murphy
Carly
C
Radtke
Ina
I
Downing
James R
JR
Fleming
Mark D
MD
MacConaill
Laura E
LE
Amatruda
James F
JF
Gutierrez
Alejandro
A
Galinsky
Ilene
I
Stone
Richard M
RM
Ross
Eric A
EA
Pellman
David S
DS
Kanki
John P
JP
Look
A Thomas
AT
D000818:Animals; D017209:Apoptosis; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000378:metabolism*; D048429:Cell Size; D004249:DNA Damage; D004625:Embryo, Nonmammalian / Q000002:abnormalities / Q000473:pathology; D047108:Embryonic Development / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D006410:Hematopoiesis; D009154:Mutation / Q000235:genetics; D022423:Myeloid Cells / Q000473:pathology; D009369:Neoplasms / Q000473:pathology*; D010641:Phenotype; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*; D015027:Zebrafish / Q000196:embryology* / Q000235:genetics*; D029961:Zebrafish Proteins / Q000378:metabolism*
D018797:Cell Cycle Proteins; D016159:Tumor Suppressor Protein p53; D029961:Zebrafish Proteins; C530717:fbxo5 protein, zebrafish
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