Laboratory of Chromosome Dynamics, Institute of Molecular and Cellular Biosciences, University of Tokyo, Yayoi, Tokyo 113-0032, Japan.
Nature. 2010 Oct 7;467(7316):719-23. doi: 10.1038/nature09390. Epub 2010 Aug 25.
Successful partition of replicated genomes at cell division requires chromosome attachment to opposite poles of mitotic spindle (bi-orientation). Any defects in this regulation bring about chromosomal instability, which may accelerate tumour progression in humans. To achieve chromosome bi-orientation at prometaphase, the chromosomal passenger complex (CPC), composed of catalytic kinase Aurora B and regulatory components (INCENP, Survivin and Borealin), must be localized to centromeres to phosphorylate kinetochore substrates. Although the CPC dynamically changes the subcellular localization, the regulation of centromere targeting is largely unknown. Here we isolated a fission yeast cyclin B mutant defective specifically in chromosome bi-orientation. Accordingly, we identified Cdk1 (also known as Cdc2)-cyclin-B-dependent phosphorylation of Survivin. Preventing Survivin phosphorylation impairs centromere CPC targeting as well as chromosome bi-orientation, whereas phosphomimetic Survivin suppresses the bi-orientation defect in the cyclin B mutant. Survivin phosphorylation promotes direct binding with shugoshin, which we now define as a conserved centromeric adaptor of the CPC. In human cells, the phosphorylation of Borealin has a comparable role. Thus, our study resolves the conserved mechanisms of CPC targeting to centromeres, highlighting a key role of Cdk1-cyclin B in chromosome bi-orientation.
细胞分裂时，为了成功分离复制的基因组，染色体必须附着到有丝分裂纺锤体的两极（双定向）。这种调节的任何缺陷都会导致染色体不稳定，从而可能加速人类肿瘤的进展。为了在早前期实现染色体的双定向，由催化激酶 Aurora B 和调节成分（INCENP、Survivin 和 Borealin）组成的染色体乘客复合物（CPC）必须定位于着丝粒，以磷酸化动粒底物。尽管 CPC 会动态改变亚细胞定位，但着丝粒靶向的调节在很大程度上仍是未知的。在这里，我们分离出一种裂殖酵母周期蛋白 B 突变体，该突变体专门在染色体双定向中存在缺陷。相应地，我们鉴定出 Cdk1（也称为 Cdc2）-cyclin-B 依赖性 Survivin 磷酸化。阻止 Survivin 磷酸化会损害着丝粒 CPC 靶向和染色体双定向，而磷酸化模拟 Survivin 则抑制周期蛋白 B 突变体的双定向缺陷。Survivin 磷酸化促进与 shugoshin 的直接结合，我们现在将其定义为 CPC 的保守着丝粒衔接蛋白。在人类细胞中，Borealin 的磷酸化具有类似的作用。因此，我们的研究解决了 CPC 靶向着丝粒的保守机制，突出了 Cdk1-cyclin B 在染色体双定向中的关键作用。
