Loading and unloading: orchestrating centrosome duplication and spindle assembly by Ran/Crm1.

Abstract

The cell cycle is an intricate process of DNA replication and cell division that concludes with the formation of two genetically equivalent daughter cells. In this progression, the centrosome is duplicated once and only once during the G1/S transition to produce the bipolar spindle and ensure proper chromosome segregation. The presence of multiple centrosomes in cancer cells suggests that this process is mis-regulated during carcinogenesis. This suggests that certain factors exist that license the progression of centrosome duplication and serve to inhibit further duplications during a single cell cycle. Recent studies suggest that the Ran/Crm1 complex not only regulates nucleocytoplasmic transport but is also independently involved in mitotic spindle assembly. Factors that are capable of interacting with Ran/Crm1 through their nuclear export sequences, such as cyclins/cdks, p53 and Brca1/2, may potentially function as centrosome checkpoints akin to the G1/S and G2/M checkpoints of the cell cycle. Our recent findings indicate that nucleophosmin, a protein whose trafficking is mediated by the Ran/Crm1 network, is one of such checkpoint factors for maintaining proper centrosome duplication. We propose that Ran/Crm1 may act as a 'loading dock' to coordinate various checkpoint factors in regulating the fidelity of centrosome duplication during cell cycle progression, and the disruption of these processes may lead to genomic instability and an acceleration of oncogenesis.