Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase.
Kinetochore life histories reveal an Aurora-B-dependent error correction mechanism in anaphase.
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DOI：
10.1016/j.devcel.2021.10.007
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发表时间：
2021-11-22
影响因子：
11.8
通讯作者：
McAinsh AD
中科院分区：
文献类型：
--
作者：
Sen O;Harrison JU;Burroughs NJ;McAinsh AD
有丝分裂过程中的染色体错误分离导致非整倍体，这是癌症的标志，与癌症基因组进化有关。错误可以在后期表现为“滞后染色体”，尽管它们的机制起源和纠正的可能性尚不完全清楚。在这里，我们结合了点阵光片显微镜、内源性蛋白标记和计算分析来定义>104着丝点的生活史。通过定义着丝点后期的“惰性”，我们发现染色体存在相当大的错误分离风险。我们发现，大多数惰性着丝点在后期被Aurora B快速纠正；如果不加以纠正，它们会导致更高的微核形成率。对着丝粒生活史的定量分析揭示了中期着丝粒振荡的动态特征，预测了它们的后期命运。我们提出，在二倍体人类细胞中，染色体分离从根本上来说是容易出错的，为了稳定的核型繁殖，需要额外的后期错误校正层。染色体处于相当大且持续的错误分离风险中，中期动力学预测惰性着丝点及其在后期的校正极光B纺锤体中间区梯度使着丝点底物磷酸化，结果表明中间区起源于极光B的活性使错误的附着不稳定。Harrison等人揭示，有丝分裂染色体的错误分离风险比之前认识到的要大。他们发现了一种对抗这种错误分离的后期错误纠正机制，并表明着丝点在后期之前的行为可以预测未来的分离结果。
Chromosome mis-segregation during mitosis leads to aneuploidy, which is a hallmark of cancer and linked to cancer genome evolution. Errors can manifest as “lagging chromosomes” in anaphase, although their mechanistic origins and likelihood of correction are incompletely understood. Here, we combine lattice light-sheet microscopy, endogenous protein labeling, and computational analysis to define the life history of >104 kinetochores. By defining the “laziness” of kinetochores in anaphase, we reveal that chromosomes are at a considerable risk of mis-segregation. We show that the majority of lazy kinetochores are corrected rapidly in anaphase by Aurora B; if uncorrected, they result in a higher rate of micronuclei formation. Quantitative analyses of the kinetochore life histories reveal a dynamic signature of metaphase kinetochore oscillations that forecasts their anaphase fate. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with an additional layer of anaphase error correction required for stable karyotype propagation. Chromosomes are at a considerable and continual risk of mis-segregation Metaphase dynamics forecast lazy kinetochores and their correction in anaphase Aurora B spindle midzone gradient enables phosphorylation of kinetochore substrates Results suggest midzone originated Aurora B activity destabilizes erroneous attachments By tracking human kinetochores from prometaphase to late anaphase, Sen, Harrison et al. reveal that mitotic chromosomes are at a greater risk of mis-segregation than previously appreciated. They uncover an anaphase error correction mechanism that combats this mis-segregation and show that kinetochore behavior before anaphase can predict future segregation outcome.
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影响因子：
21.3
作者：
Bakhoum, Samuel F.;Thompson, Sarah L.;Manning, Amity L.;Compton, Duane A.
通讯作者：
Compton, Duane A.
DOI：
10.1126/science.1251121
发表时间：
2014-07-18
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Afonso O;Matos I;Pereira AJ;Aguiar P;Lampson MA;Maiato H
通讯作者：
Maiato H
影响因子：
64.8
作者：
Fuller, Brian G.;Lampson, Michael A.;Kapoor, Tarun M.
通讯作者：
Kapoor, Tarun M.
影响因子：
4.3
作者：
Armond JW;Harry EF;McAinsh AD;Burroughs NJ
通讯作者：
Burroughs NJ
DOI：
10.1083/jcb.201506011
发表时间：
2016-03-28
期刊：
The Journal of cell biology
影响因子：
--
作者：
Cojoc G;Roscioli E;Zhang L;García-Ulloa A;Shah JV;Berns MW;Pavin N;Cimini D;Tolić IM;Gregan J
通讯作者：
Gregan J