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Published online 14 June 2004. doi:10.1083/jcb.200404092
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 6, 789-800
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Article

Deregulation of cyclin E in human cells interferes with prereplication complex assembly



Susanna Ekholm-Reed1,3, Juan Méndez2, Donato Tedesco1, Anders Zetterberg3, Bruce Stillman2, and Steven I. Reed1

1 Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA 92037
2 Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724
3 Department of Oncology-Pathology, Cancer Center Karolinska, 171 76 Stockholm, Sweden

Address correspondence to Susanna Ekholm-Reed, Dept. of Molecular Biology, MB-7, The Scripps Research Institute, 10550 N. Torrey Pines Rd., La Jolla, CA 92037. Tel.: (858) 784-9836. Fax: (858) 784-2781. email: sreed{at}scripps.edu

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.

Key Words: cyclin E; MCM protein; prereplication complex assembly; DNA replication; cyclin E deregulation

S. Ekholm-Reed and J. Méndez contributed equally to this paper.

The online version of this article includes supplemental material.

Abbreviations used in this paper: c-Ad, control adenovirus; E-Ad, cyclin E recombinant adenovirus; MCM, minichromosome maintenance complex; ORC, origin recognition complex; PCNA, proliferating cell nuclear antigen; preRC, prereplication complex; siRNA, small interfering RNA.


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