Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms
Kinetochore life histories reveal the origins of chromosome mis-segregation and correction mechanisms
复制标题
动粒生命史揭示了染色体错误分离的起源和纠正机制
DOI：
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发表时间：
2021
期刊：
影响因子：
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通讯作者：
A. McAinsh
中科院分区：
文献类型：
--
作者：
Onur Sen;Jonathan U. Harrison;N. Burroughs;A. McAinsh
有丝分裂过程中染色体的错误分离导致子代细胞核型异常(非整倍体)，并通过错误分离的染色体的染色质增加突变负担。错分率和非整倍体状态是癌症的标志，与癌症基因组进化有关。错误可能在后期表现为“落后的染色体”，尽管机制起源和纠正的可能性还不完全清楚。在这里，我们结合晶格光片显微镜、内源蛋白质标记和计算分析来定义超过200个细胞的中期和后期动粒的生活史。通过定义后期着丝点的“懒惰”，我们揭示了染色体处于相当大的和持续的错误分离的风险。我们表明，大多数动点在早期和后期通过Aurora B依赖的过程被迅速纠正。此外，对动粒生活史的定量分析揭示了一个独特的中期动粒振荡的动态特征，该特征预测了它们在随后的后期的命运。我们认为，在二倍体人类细胞中，染色体分离从根本上是容易出错的，需要一层新的早期后期误差校正才能实现稳定的核型繁殖。
Chromosome mis-segregation during mitosis leads to daughter cells with deviant karyotypes (aneuploidy) and an increased mutational burden through chromothripsis of mis-segregated chromosomes. The rate of mis-segregation and the aneuploidy state are hallmarks of cancer and linked to cancer genome evolution. Errors can manifest as “lagging chromosomes” in anaphase, although the mechanistic origins and likelihood of correction are incompletely understood. Here we combine lattice light sheet microscopy, endogenous protein labelling and computational analysis to define the life history of > 104 kinetochores throughout metaphase and anaphase from over 200 cells. By defining the “laziness” of kinetochores in anaphase, we reveal that chromosomes are at a considerable and continual risk of mis-segregation. We show that the majority of kinetochores are corrected rapidly in early anaphase through an Aurora B dependent process. Moreover, quantitative analyses of the kinetochore life histories reveal a unique dynamic signature of metaphase kinetochore oscillations that forecasts their fate in the subsequent anaphase. We propose that in diploid human cells chromosome segregation is fundamentally error prone, with a new layer of early anaphase error correction required for stable karyotype propagation.
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