Sci. Signal., 25 November 2008
Cell Cycle Quality Attachments
Science Signaling, AAAS, Washington, DC 20005, USA
The mitotic checkpoint is a quality-control mechanism designed to prevent cells with misaligned chromosomes from completing mitosis. At the kinetochore, the kinase budding uninhibited benzimidazole receptor 1 (BubR1), which is key to this checkpoint, monitors that chromosome kinetochores are attached to microtubules in the mitotic spindle. Downstream of the kinetochore, BubR1 inhibits the anaphase-promoting complex/cyclosome (APC/C), which degrades the proteins that hold the sister chromatids together until the chromosomes have aligned properly. Huang et al. now demonstrate that the phosphorylation status of four serine residues in BubR1—Ser453, Ser543, Ser670, and Ser1043 (human numbering)—link BubR1s roles at and downstream of the kinetochore. BubR1 was phosphorylated at these four sites when kinetochores were attached to microtubules in metaphase. Dephosphorylation of these residues occurred at the onset of anaphase, when the kinetochores were no longer attached to microtubules. In cells that expressed BubR1 with mutations that either prevented phosphorylation or mimicked phosphorylation at all four residues or only at Ser670, the most conserved of these residues in vertebrates, kinetochore-microtubule attachments, failed to generate tension, likely contributing to delays in metaphase-to-anaphase progression. This metaphase delay was also observed in cells injected with antibodies that recognized phosphorylated Ser670 or phosphorylated Ser1043 of BubR1 and that were thought to delay dephosphorylation of these residues. Furthermore, the phosphoSer670 antibody delayed activation of APC/C and thus affected mitotic checkpoint events downstream of the kinetochore, suggesting that the phosphorylation status of BubR1 at Ser670 is linked to its ability to inhibit APC/C. The authors proposed that BubR1 remains phosphorylated at serines 453, 543, 670, and 1043 until the chromosomes develop enough tension on the mitotic spindle, at which point BubR1 becomes dephosphorylated and ceases to inhibit APC/C, allowing mitosis to proceed. Noting that phosphorylation of BubR1 at these serine residues was carried out primarily but not exclusively by monopolar spindle 1 (Mps1), the authors speculated that BubR1 may serve as an integration point at the mitotic checkpoint for signals from Mps1 and other cell cycle progression kinases.
H. Huang, J. Hittle, F. Zappacosta, R. S. Annan, A. Hershko, T. J. Yen, Phosphorylation sites in BubR1 that regulate kinetochore attachment, tension, and mitotic exit. J. Cell Biol. 183, 667–680 (2008). [Abstract] [Full Text]
Citation: W. Wong, Quality Attachments. Sci. Signal. 1, ec407 (2008).
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