title: Deregulation of cyclin E in human cells interferes with prereplication complex assembly.
abstract: Deregulation of cyclin E expression has been associated with a broad spectrum of human malignancies. Analysis of DNA replication in cells constitutively expressing cyclin E at levels similar to those observed in a subset of tumor-derived cell lines indicates that initiation of replication and possibly fork movement are severely impaired. Such cells show a specific defect in loading of initiator proteins Mcm4, Mcm7, and to a lesser degree, Mcm2 onto chromatin during telophase and early G1 when Mcm2-7 are normally recruited to license origins of replication. Because minichromosome maintenance complex proteins are thought to function as a heterohexamer, loading of Mcm2-, Mcm4-, and Mcm7-depleted complexes is likely to underlie the S phase defects observed in cyclin E-deregulated cells, consistent with a role for minichromosome maintenance complex proteins in initiation of replication and fork movement. Cyclin E-mediated impairment of DNA replication provides a potential mechanism for chromosome instability observed as a consequence of cyclin E deregulation.
authors.affiliation: Dept. of Molecular Biology, MB-7, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037, USA. sreed@scripps.edu
authors.forename: Susanna
authors.initials: S
authors.lastname: Ekholm-Reed
authors.forename: Juan
authors.initials: J
authors.lastname: Méndez
authors.forename: Donato
authors.initials: D
authors.lastname: Tedesco
authors.forename: Anders
authors.initials: A
authors.lastname: Zetterberg
authors.forename: Bruce
authors.initials: B
authors.lastname: Stillman
authors.forename: Steven I
authors.initials: SI
authors.lastname: Reed
mesh_terms: D001943:Breast Neoplasms; D018797:Cell Cycle Proteins / Q000235:genetics; D045744:Cell Line, Tumor; D019927:Cyclin E / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication / Q000235:genetics / Q000502:physiology*; D004268:DNA-Binding Proteins / Q000172:deficiency / Q000235:genetics; D005260:Female; D005434:Flow Cytometry; D016193:G1 Phase; D006801:Humans; D007624:KB Cells; D064111:Minichromosome Maintenance Complex Component 2; D064148:Minichromosome Maintenance Complex Component 4; D064168:Minichromosome Maintenance Complex Component 7; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; D019927:Cyclin E; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C099243:MCM4 protein, human; C101624:MCM7 protein, human; D064111:Minichromosome Maintenance Complex Component 2; D064148:Minichromosome Maintenance Complex Component 4; D064168:Minichromosome Maintenance Complex Component 7