CYCLIN E CDK2

Cyclin E-Cdk2 is known to regulate both DNA replication and centrosome duplication during the G1-S transition in the cell cycle, and disruption of centrosome results in a G1 arrest in some cell types. It is a catalytic subunit of the Cyclin dependent kinase complex, whose activity is restricted to the G1-phase of the cell cycle, and is essential for the G1 S transition. Cyclin E binds G1 phase Cdk2, which is required for the transition from G1 to S phase. Its activity is regulated by phosphorylation. Centrosomes are the primary microtubule-organizing centers in animal cells and are required for bipolar spindle assembly during mitosis. Amplification of centrosome number is commonly observed in human cancer cells and might contribute to genomic instability. Cyclin ECdk2 has been implicated in regulating centrosome duplication both in Xenopus embryos and extracts and in mammalian cells. Localization of cyclin E on centrosomes is mediated by a 20amino acid domain termed the centrosomal localization sequence (CLS). Cyclin E Cdk2 rise in late G1 and fall in early S phase. The Cdk- G1/S cyclin complex begins to induce the initial processes of DNA replication, primarily by arresting systems that prevent S phase Cdk activity in G1. The cyclins also promote other activities to progress the cell cycle, like centrosome duplication in vertebrates or spindle pole body in yeast. The rise in presence of G1/S cyclins is paralleled by a rise in S cyclins. S cyclins bind to Cdk and the complex directly induces DNA replication. The levels of S cyclins remain high, not only throughout S phase, but through G2 and early mitosis as well to promote early events in mitosis. Localization of cyclin E on centrosome is mediated by a 20 amino acid domain termed the Centrosome Localization Sequence (CLS). The loading of essential DNA replication factors such as Cdc45 and proliferating cell nuclear antigen onto chromatin is blocked by CLS expression, but DNA synthesis can be rescued by retargeting active cyclin E-Cdk2 to the centrosome. These results suggest that initial steps of DNA replication require centrosomally localized Cdk activity and link the nuclear cycle with the centrosome cycle at the G1-S transition.