Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, UK; Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry, UK.
Centre for Mechanochemical Cell Biology, University of Warwick, Coventry, UK; Mathematics Institute and Zeeman Institute, University of Warwick, Coventry, UK.
Dev Cell. 2021 Nov 22;56(22):3082-3099.e5. doi: 10.1016/j.devcel.2021.10.007. Epub 2021 Nov 9.
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 >10 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.
有丝分裂过程中染色体的错误分离会导致非整倍体，这是非典型性癌症的一个标志，与癌症基因组的演变有关。错误可能表现为后期的“滞后染色体”，尽管其机制起源和校正的可能性尚不完全清楚。在这里，我们将晶格层光片显微镜、内源性蛋白标记和计算分析相结合，定义了>10 个着丝粒的生命史。通过定义后期着丝粒的“懒惰性”，我们揭示了染色体有很高的错误分离风险。我们发现，大多数后期的懒惰着丝粒可以通过 Aurora B 迅速校正；如果未被校正，它们会导致更高的微核形成率。对着丝粒生命史的定量分析揭示了中期着丝粒振荡的动态特征，该特征预测了它们后期的命运。我们提出，在二倍体人类细胞中，染色体分离从根本上是容易出错的，需要在后期进行额外的错误校正层，以确保稳定的核型传播。
