Bub3’s function doesn’t stop at the checkpoint

Morais da Silva et al. show that the checkpoint protein Bub3 suppresses tumorigenesis independently of its role in chromosome segregation.

The spindle assembly checkpoint prevents cells from entering anaphase until all their chromosomes are correctly attached to the mitotic spindle, thereby avoiding chromosome missegregation and aneuploidy. Aneuploidy is widely thought to drive tumorigenesis, but whether the loss of checkpoint proteins contributes to tumor progression is unclear.

Morais da Silva et al. knocked down the checkpoint protein Bub3 in the developing wings of Drosophila larvae. Cells lacking Bub3 missegregated their chromosomes and died, but when the researchers overexpressed an anti-apoptotic protein to keep them alive, the cells hyperproliferated and formed tumors when transplanted into the abdomens of adult flies.

Though the Bub3 and apoptosis-deficient cells were aneuploid, missegregated chromosomes weren’t the cause of these tumors. When Morais da Silva et al. induced aneuploidy by knocking down CENP-E—a kinesin motor that helps attach spindle microtubules to kinetochores—Drosophila wing cells didn’t hyperproliferate even when apoptosis was inhibited. In addition, when the researchers blocked apoptosis and knocked down the kinetochore protein Nsl1, Bub3 was no longer recruited to kinetochores, and the spindle checkpoint was impaired. Yet these cells didn’t form tumors unless the cytoplasmic pool of Bub3 was also depleted.

This suggests that, rather than suppressing tumorigenesis via the spindle checkpoint, Bub3 has an additional function that limits cell proliferation. The authors now want to determine what this extra function might be.