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Small molecule inhibitors of Aurora B activity, characterized by Hauf et al. (page 281) and Ditchfield et al. (page 267), reveal that the mammalian kinase and its budding yeast counterpart, Ipl1, have similar functions. Without Aurora B, mistakes in kinetochore–chromosome interactions go uncorrected.( v- s$ Z4 l* I0 b
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Early evidence of a function for the Aurora family in correcting syntelic attachments, those in which both chromatids are attached to the same spindle pole, was provided by the ipl1 mutant. But visualizing spindle–kinetochore attachments in yeast is difficult. The two articles in this issue examine attachments directly, by inhibiting Aurora B in mammalian cells.
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, {, ]! \6 _( _6 WThe groups used different compounds, but in both cases the Aurora B inhibitors left chromosomes misaligned and compromised the spindle checkpoint, thus causing division failure and endoreduplication. Hauf et al. saw that syntelic attachments were more common in inhibitor-treated cells. They hypothesize that Aurora B senses the lack of tension between syntelic sister chromatids and destabilizes either one or both so that correct attachments can be established. If the checkpoint is activated by unattached kinetochores, its override by Aurora B inhibition may be an indirect result of stable syntelic attachments. Indeed, drugs that destabilize microtubules restored checkpoint function in the presence of the inhibitors, at least in the short term.
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2 ?: X9 r1 C0 g3 O+ Y3 `Aurora B may also have a more direct effect on the spindle checkpoint through BubR1 or other kinetochore proteins. Low tension between sister chromatids normally leads to recruitment of BubR1 to kinetochores. But BubR1 was absent from kinetochores in the presence of either inhibitor. Ditchfield et al. show that RNA interference of BubR1 caused a chromosome alignment defect resembling that seen in cells treated with their Aurora B inhibitor. It is possible that BubR1 not only monitors kinetochore–microtubule interactions but also regulates them in response to changes in Aurora B activity.(Inhibition of Aurora B causes misalignme) |
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发表于 2009-3-6 00:39
发表于 2015-6-9 12:58
