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CDK phosphorylation of a novel NLS-NES module distributed between two subunits of the Mcm2-7 complex prevents chromosomal rereplication.

Cyclin-dependent kinases (CDKs) use multiple mechanisms to block reassembly of prereplicative complexes (pre-RCs) at replication origins to prevent inappropriate rereplication. In Saccharomyces cerevisiae, one of these mechanisms promotes the net nuclear export of a pre-RC component, the Mcm2-7 complex, during S, G2, and M phases. Here we identify two partial nuclear localization signals (NLSs) on Mcm2 and Mcm3 that are each necessary, but not sufficient, for nuclear localization of the Mcm2-7 complex. When brought together in cis, however, the two partial signals constitute a potent NLS, sufficient for robust nuclear localization when fused to an otherwise cytoplasmic protein. We also identify a Crm1-dependent nuclear export signal (NES) adjacent to the Mcm3 NLS. Remarkably, the Mcm2-Mcm3 NLS and the Mcm3 NES are sufficient to form a transport module that recapitulates the cell cycle-regulated localization of the entire Mcm2-7 complex. Moreover, we show that CDK regulation promotes net export by phosphorylation of the Mcm3 portion of this module and that nuclear export of the Mcm2-7 complex is sufficient to disrupt replication initiation. We speculate that the distribution of partial transport signals among distinct subunits of a complex may enhance the specificity of protein localization and raises the possibility that previously undetected distributed transport signals are used by other multiprotein complexes.

Pubmed ID: 16093348 RIS Download

Mesh terms: Amino Acid Sequence | CDC28 Protein Kinase, S cerevisiae | Cell Cycle | Cell Cycle Proteins | Chromosomal Proteins, Non-Histone | Chromosomes, Fungal | DNA Replication | DNA-Binding Proteins | Fungal Proteins | Karyopherins | Minichromosome Maintenance Complex Component 3 | Minichromosome Maintenance Complex Component 4 | Minichromosome Maintenance Complex Component 6 | Minichromosome Maintenance Complex Component 7 | Molecular Sequence Data | Nuclear Localization Signals | Nuclear Proteins | Phosphorylation | Protein Subunits | Protein Transport | Receptors, Cytoplasmic and Nuclear | Saccharomyces cerevisiae | Saccharomyces cerevisiae Proteins

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Associated grants

  • Agency: NCI NIH HHS, Id: 1 F31 CA110268-01
  • Agency: NCI NIH HHS, Id: T32 CA009270
  • Agency: NCI NIH HHS, Id: T32 CA09270
  • Agency: NIGMS NIH HHS, Id: 1 R25 GM56847
  • Agency: NIGMS NIH HHS, Id: R01 GM59704
  • Agency: NIGMS NIH HHS, Id: R25 GM056847
  • Agency: NCI NIH HHS, Id: F31 CA110268
  • Agency: NIGMS NIH HHS, Id: R01 GM059704

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