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

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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.