Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation

doi:10.1083/jcb.200211048

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Published online 27 January 2003. doi:10.1083/jcb.200211048

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© The Rockefeller University Press, 0021-9525/2003/2/341 $5.00
The Journal of Cell Biology, Volume 160, Number 3, 341-353

Article

Rae1 is an essential mitotic checkpoint regulator that cooperates with Bub3 to prevent chromosome missegregation

J. Ramesh Babu, Karthik B. Jeganathan, Darren J. Baker, Xiaosheng Wu, Ningling Kang-Decker and Jan M. van Deursen

Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN 55905

Address correspondence to Jan van Deursen, Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Tel.: 507-284-2524. Fax: 507-266-0340. E-mail: vandeursen.jan{at}mayo.edu

The WD-repeat proteins Rae1 and Bub3 show extensive sequencehomology, indicative of functional similarity. However, previousstudies have suggested that Rae1 is involved in the mRNA exportpathway and Bub3 in the mitotic checkpoint. To determine thein vivo roles of Rae1 and Bub3 in mammals, we generated knockoutmice that have these genes deleted individually or in combination.Here we show that haplo-insufficiency of either Rae1 or Bub3results in a similar phenotype involving mitotic checkpointdefects and chromosome missegregation. We also show that overexpressionof Rae1 can correct for Rae1 haplo-insufficiency and, surprisingly,Bub3 haplo-insufficiency. Rae1-null and Bub3-null mice are embryoniclethal, although cells from these mice did not have a detectabledefect in nuclear export of mRNA. Unlike null mice, compoundhaplo-insufficient Rae1/Bub3 mice are viable. However, cellsfrom these mice exhibit much greater rates of premature sisterchromatid separation and chromosome missegregation than singlehaplo-insufficient cells. Finally, we show that mice with mitoticcheckpoint defects are more susceptible to dimethylbenzanthrene-inducedtumorigenesis than wild-type mice. Thus, our data demonstratea novel function for Rae1 and characterize Rae1 and Bub3 asrelated proteins with essential, overlapping, and cooperatingroles in the mitotic checkpoint.

Key Words: mRNA export; Rae1/Gle2; Bub3; mitotic checkpoint; chromosomal instability

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