Molecular mechanism underlying the breakdown of chromosomal homeostasis by aberrant activation of cyclin A-CDK

细胞周期蛋白A(Cyclin A，Cyclin A)-CDK复合体的异常激活是哺乳动物细胞周期进程的中枢调控因子之一，通过与复制起始因子MCM7相互作用，加速进入DNA复制期(S期)，并诱导中心体过度复制和染色体四倍化，从而破坏染色体的动态平衡，从而导致肿瘤的发生。在本研究中，我们分析了上述现象的分子机制及其相关性，揭示了(1)Cyca和MCM7同时与人类细胞中的染色体复制起始区结合；(2)Cyca-CDK的异常激活通过一条未知的途径诱导了染色体的四倍化，该途径不涉及中心体复制和染色体分离的调节因子Mps1；(3)Cyca促进S相进入的功能不参与染色体的四倍化。

Aberrant activation of cyclin A (CycA)-CDK complex, one of the central regulatory factors for mammalian cell cycle progression, leads to the acceleration of entry into DNA replication phase (S phase) via interaction with a replication initiation factor Mcm7 and the induction of centrosomal overduplication and chromosomal tetraploidization, which both could contribute to a breakdown of chromosomal homeostasis and to carcinogenesis. In this study we analyzed the molecular mechanisms and correlation of the aforementioned phenomena, and revealed that (1) CycA and Mcm7 simultaneously bind to chromosomal replication initiation regions in human cells, (2) aberrant activation of CycA-CDK induces the chromosome tetraploidization via an unknown pathway not involving Mps1, a regulatory factor for the centrosomal duplication and chromosomal segregation, and (3) the CycA function promoting S-phase entry is not involved in chromosomal tetraploidization.