The MOE Key Laboratory of Cell Proliferation and Differentiation and the State Key Laboratory of Membrane Biology, College of Life Sciences, Peking University, Beijing 100871, China.
Nat Commun. 2017 Apr 27;8:15164. doi: 10.1038/ncomms15164.
Centrosome number is tightly controlled during the cell cycle to ensure proper spindle assembly and cell division. However, the underlying mechanism that controls centrosome number remains largely unclear. We show herein that the DNA replication licensing factor Cdc6 is recruited to the proximal side of the centrioles via cyclin A to negatively regulate centrosome duplication by binding and inhibiting the cartwheel protein Sas-6 from forming a stable complex with another centriole duplication core protein, STIL. We further demonstrate that Cdc6 colocalizes with Plk4 at the centrosome, and interacts with Plk4 during S phase. Plk4 disrupts the interaction between Sas-6 and Cdc6, and suppresses the inhibitory role of Cdc6 on Sas-6 by phosphorylating Cdc6. Overexpressing wild-type Cdc6 or Plk4-unphosphorylatable Cdc6 mutant 2A reduces centrosome over-duplication caused by Plk4 overexpression or hydroxyurea treatment. Taken together, our data demonstrate that Cdc6 and Plk4 antagonistically control proper centrosome duplication during the cell cycle.
中心体的数量在细胞周期中受到严格控制，以确保纺锤体的正确组装和细胞分裂。然而，控制中心体数量的潜在机制在很大程度上仍不清楚。我们在此表明，DNA 复制许可因子 Cdc6 通过细胞周期蛋白 A 被招募到中心粒的近端，通过结合并抑制车轮蛋白 Sas-6 与另一个中心粒复制核心蛋白 STIL 形成稳定复合物，从而负调控中心体复制。我们进一步证明，Cdc6 与 Plk4 在中心体共定位，并在 S 期与 Plk4 相互作用。Plk4 破坏了 Sas-6 和 Cdc6 之间的相互作用，并通过磷酸化 Cdc6 抑制 Cdc6 对 Sas-6 的抑制作用。过表达野生型 Cdc6 或 Plk4 不可磷酸化的 Cdc6 突变体 2A 可减少由 Plk4 过表达或羟基脲处理引起的中心体过度复制。总之，我们的数据表明，Cdc6 和 Plk4 在细胞周期中拮抗地控制适当的中心体复制。
