Cyclin E-dependent localization of MCM5 regulates centrosome duplication.
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 E-Cdk2 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 20-amino acid domain termed the centrosomal localization sequence (CLS). In this paper, cyclin E is shown to directly interact with and colocalize on centrosomes with the DNA replication factor MCM5 in a CLS-dependent but Cdk2-independent manner. The domain in MCM5 that is responsible for interaction with cyclin E is distinct from any previously described for MCM5 function and is highly conserved in MCM5 proteins from yeast to mammals. Expression of MCM5 or its cyclin E-interacting domain, but not MCM2, significantly inhibits over-duplication of centrosomes in CHO cells arrested in S-phase. These results indicate that proteins involved in DNA replication might also regulate centrosome duplication.
Ferguson
Rebecca L
RL
Howard Hughes Medical Institute and Program in Molecular Biology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
Maller
James L
JL
D000595:Amino Acid Sequence; D000818:Animals; D016466:CHO Cells; D018797:Cell Cycle Proteins / Q000737:chemistry / Q000378:metabolism*; D018385:Centrosome / Q000378:metabolism*; D006224:Cricetinae; D003412:Cricetulus; D019927:Cyclin E / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D064111:Minichromosome Maintenance Complex Component 2; D008954:Models, Biological; D008969:Molecular Sequence Data; D009687:Nuclear Proteins / Q000378:metabolism; D015513:Oncogene Proteins / Q000378:metabolism*; D011485:Protein Binding; D021382:Protein Sorting Signals; D017434:Protein Structure, Tertiary; D021381:Protein Transport
C475820:CCNE1 protein, human; D018797:Cell Cycle Proteins; D019927:Cyclin E; C489423:MCM5 protein, human; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D021382:Protein Sorting Signals; C084859:MCM2 protein, human; D064111:Minichromosome Maintenance Complex Component 2