Abstract
RINGO/Speedy proteins are direct activators of Cdk1 and Cdk2 that have no sequence homology to cyclins. We have characterized the role in cell-cycle progression of a new human member of this protein family referred to as RINGO C. We show that siRNA-mediated knockdown of RINGO C results in premature mitotic exit with misaligned chromosomes, even in the presence of microtubule poisons. Time-lapse-microscopy experiments suggest that RINGO C is involved in the spindle-assembly checkpoint (SAC). Consistent with this idea, RINGO-C-depleted cells show impaired recruitment of the SAC components Mad2, Bub1 and BubR1. As the checkpoint is overridden, cells display defective chromosome segregation, which leads to an increased number of micronuclei and binucleated structures. Intriguingly, we found that RINGO C can associate with the mitotic kinase Aurora B, and downregulation of RINGO C produces mislocalization of the active form of Aurora B in prometaphase. Taken together, our results indicate a role for RINGO C in the mitotic checkpoint, which might be mediated by defective recruitment of SAC components and deregulation of the activity of Aurora kinase B.
Highlights
Since mitosis was first described in the 1880s, scientists have tried to understand the molecular basis of chromosome segregation and the mechanisms that ensure genomic stability
We show that siRNAmediated knockdown of RINGO C results in premature mitotic exit with misaligned chromosomes, even in the presence of microtubule poisons
Time-lapse-microscopy experiments suggest that RINGO C is involved in the spindle-assembly checkpoint (SAC)
Summary
Since mitosis was first described in the 1880s, scientists have tried to understand the molecular basis of chromosome segregation and the mechanisms that ensure genomic stability. The spindle-assembly checkpoint (SAC) is a cellcycle control mechanism that ensures the fidelity of chromosome segregation during mitosis by preventing premature entry into anaphase. This signal-transduction network is highly conserved from yeast to man, and includes the Mad, Bub and Mps proteins, which monitor different aspects of kinetochore-spindle interactions such as proper attachment between them or defects in the tension exerted by microtubule-generated forces on kinetochores (for reviews, see Kops et al, 2005; Musacchio and Salmon, 2007). Genetic mutation or changes in the expression levels of proteins such as BubR1 and Mad are associated with chromosomal instability (Cahill et al, 1998; Hanks et al, 2004; Kops et al, 2005; Shichiri et al, 2002)
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