Bub1 regulates chromosome segregation in a kinetochore-independent manner.
The kinetochore-bound protein kinase Bub1 performs two crucial functions during mitosis: it is essential for spindle checkpoint signaling and for correct chromosome alignment. Interestingly, Bub1 mutations are found in cancer tissues and cancer cell lines. Using an isogenic RNA interference complementation system in transformed HeLa cells and untransformed RPE1 cells, we investigate the effect of structural Bub1 mutants on chromosome segregation. We demonstrate that Bub1 regulates mitosis through the same mechanisms in both cell lines, suggesting a common regulatory network. Surprisingly, Bub1 can regulate chromosome segregation in a kinetochore-independent manner, albeit at lower efficiency. Its kinase activity is crucial for chromosome alignment but plays only a minor role in spindle checkpoint signaling. We also identify a novel conserved motif within Bub1 (amino acids 458-476) that is essential for spindle checkpoint signaling but does not regulate chromosome alignment, and we show that several cancer-related Bub1 mutants impair chromosome segregation, suggesting a possible link to tumorigenesis.
Klebig
Christiane
C
Institute of Biochemistry, Eidgenössische Technische Hochschule (ETH) Zurich, 8093 Zurich, Switzerland.
Korinth
Dirk
D
Meraldi
Patrick
P
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D020090:Chromosome Segregation / Q000235:genetics / Q000502:physiology*; D002877:Chromosomes, Human / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D018386:Kinetochores / Q000378:metabolism / Q000502:physiology; D008938:Mitosis / Q000502:physiology; D008969:Molecular Sequence Data; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D034622:RNA Interference; D015398:Signal Transduction
C584277:BUB1 protein, human; C090464:Bub1 spindle checkpoint protein; D017346:Protein Serine-Threonine Kinases