Regulation of Geminin Functions by Cell Cycle-Dependent Nuclear-Cytoplasmic Shuttling

Abstract

The geminin protein functions both as a DNA rereplication inhibitor through association with Cdt1 and as a repressor of Hox gene transcription through the polycomb pathway. Here, we report that the functions of avian geminin are coordinated with and regulated by cell cycle-dependent nuclear-cytoplasmic shuttling. In S phase, geminin enters nuclei and inhibits both loading of the minichromosome maintenance (MCM) complex onto chromatin and Hox gene transcription. At the end of mitosis, geminin is exported from nuclei by the exportin protein Crm1 and is unavailable in the nucleus during the next G₁ phase, thus ensuring proper chromatin loading of the MCM complex and Hox gene transcription. This mechanism for regulating the functions of geminin adds to distinct mechanisms, such as protein degradation and ubiquitination, applied in other vertebrates.

We thank M. Méchali, D. Maiorano, and B. Stillman for antibodies, I. H. Su for protocols, and D. Doenecke for his continuous support on this project.

This work was funded by the Max Planck Society and DFG.