The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments
The human mitotic checkpoint protein BubR1 regulates chromosome-spindle attachments
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DOI：
10.1038/ncb1208
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发表时间：
2005-01-01
影响因子：
21.3
通讯作者：
Kapoor, TM
中科院分区：
文献类型：
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作者：
Lampson, MA;Kapoor, TM
整个染色体的丢失或获得，即染色体不稳定性（CIN）的形式，最常与人类癌症相关，预计是由于有丝分裂中染色体不能准确分离而引起的(1)。有丝分裂检查点是一种途径，通过阻止后期的开始，直到所有染色体都正确地附着在纺锤体上，防止分离错误。另一个防止错误的过程是染色体和纺锤体微管之间连接的稳定和不稳定。一个突出的问题是这两种途径如何协调以确保准确的染色体分离。在这里，我们表明，在人类细胞中，BubR1是有丝分裂检查点的关键成分，可以直接调节后期（2-4）的开始，染色体不能与纺锤体微管形成稳定的附着物。这些细胞中的附着通过抑制极光激酶恢复，已知极光激酶可以稳定着丝点-微管附着（5-7）。因此，BubR1功能的丧失扰乱了附着体的调节，而不是着丝点与微管结合的能力。与这一发现一致，BubR1的缺失增加了CENP-A的磷酸化，CENP-A是一种着丝酶特异性的极光激酶底物。我们提出BubR1将染色体纺锤体附着的调节与有丝分裂检查点信号传导联系起来。
Loss or gain of whole chromosomes, the form of chromosomal instability (CIN) most commonly associated with human cancers, is expected to arise from the failure to accurately segregate chromosomes in mitosis(1). The mitotic checkpoint is one pathway that prevents segregation errors by blocking the onset of anaphase until all chromosomes make proper attachments to the spindle. Another process that prevents errors is stabilization and destabilization of connections between chromosomes and spindle microtubules. An outstanding question is how these two pathways are coordinated to ensure accurate chromosome segregation. Here we show that in human cells depleted of BubR1 - a critical component of the mitotic checkpoint that can directly regulate the onset of anaphase(2-4) - chromosomes do not form stable attachments to spindle microtubules. Attachments in these cells are restored by inhibition of Aurora kinase, which is known to stabilize kinetochore - microtubule attachments(5-7). Loss of BubR1 function thus perturbs regulation of attachments rather than the ability of kinetochores to bind to microtubules. Consistent with this finding, depletion of BubR1 increases phosphorylation of CENP-A, a kinetochore-specific Aurora kinase substrate. We propose that BubR1 links regulation of chromosome-spindle attachment to mitotic checkpoint signalling.