Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms
Merotelic kinetochore orientation occurs frequently during early mitosis in mammalian tissue cells and error correction is achieved by two different mechanisms
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DOI：
10.1242/jcs.00716
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发表时间：
2003-10-15
影响因子：
4
通讯作者：
Salmon, ED
中科院分区：
文献类型：
--
作者：
Cimini, D;Moree, B;Salmon, ED
当单个着丝点从两个纺锤极而不是一个纺锤极附着在微管上时，就会发生分裂着丝点定向错误。我们首次获得证据表明，在哺乳动物组织细胞的早期有丝分裂过程中，分裂着丝点定向非常频繁，并且在具有双极纺锤体和未受干扰的染色体的细胞中，两种不同的校正机制对于准确的染色体分离至关重要。我们的数据显示，大约30%的前期PtK1细胞具有一个或多个细分定向的着丝点。在从诺可达唑诱导的有丝分裂阻滞中恢复的细胞中，这一频率增加到90%以上。在服用诺可达唑后恢复的细胞中，可以看到高频率的纺锤体双极性的建立延迟，而在未治疗的细胞中则没有。在未治疗的细胞中，晚期细胞中有细端取向的滞后染色体的频率为1%，在从诺可达唑中恢复的细胞中为18%。无论对未处理的细胞还是对诺可达唑处理的细胞，中期延长2小时都减少了后期细胞携带滞后染色体的频率。令人惊讶的是，后期滞后染色体只占中期后期分裂着丝点取向的很小一部分。我们的数据表明，有两种校正机制可以防止染色体因分裂着丝点方向而发生错误分离。首先，后期前的校正机制增加了着丝点微管附着在正确极与不正确极上的比例，并可能最终导致着丝点在后期开始前重新定向。微管与对极比例的增加是第二种机制的基础，这种机制在后期活跃，促进分端染色体向正确的极分离。
Merotelic kinetochore orientation is an error that occurs when a single kinetochore becomes attached to microtubules from two spindle poles rather than just to one pole. We obtained the first evidence that merotelic kinetochore orientation occurs very frequently during early mitosis in mammalian tissue cells and that two different correction mechanisms are critical for accurate chromosome segregation in cells possessing bipolar spindles and unperturbed chromosomes. Our data show that about 30% of prometaphase PtK1 cells possess one or more merotelically oriented kinetochores. This frequency is increased to over 90% in cells recovering from a nocodazole-induced mitotic block. A delay in establishing spindle bipolarity is responsible for the high frequency of merotelic orientations seen in cells recovering from nocodazole, but not in untreated cells. The frequency of anaphase cells with merotelically oriented lagging chromosomes is 1% in untreated cells and 18% in cells recovering from nocodazole. Prolonging metaphase by 2 hours reduced the frequency of anaphase cells with lagging chromosomes both for untreated and for nocodazole-treated cells. Surprisingly, anaphase lagging chromosomes represented a very small fraction of merotelic kinetochore orientations present in late metaphase. Our data indicate that two correction mechanisms operate to prevent chromosome mis-segregation due to merotelic kinetochore orientation. The first, a pre-anaphase correction mechanism increases the ratio of kinetochore microtubules attached to the correct versus incorrect pole and might eventually result in kinetochore re-orientation before anaphase onset. The increase in microtubule ratio to opposite poles is the groundwork for a second mechanism, active in anaphase, that promotes the segregation of merotelically oriented chromosomes to the correct pole.