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.

Replication stress and cancer: It takes two to tango

“…Overexpression of cyclin E reduces the number of replication origins that are licensed during G1. As a consequence, RS increases in S-phase due to the shortage of backup origins to cope with stalled forks [13]. This effect is similar to that observed in hypomorphic mutants of the components of the MCM helicase.…”

Deregulated cyclin E promotes p53 loss of heterozygosity and tumorigenesis in the mouse mammary gland

“…However, loss of the remaining p53 allele might also act synergistically to promote tumorigenesis through elevated kinase activity potentiated by abrogation of the p53/p21 pathway (Loeb et al, 2005). This may be mediated by centrosome hyperamplification (Mussman et al, 2000;Kawamura et al, 2004), perturbation of rereplication complex assembly (Ekholm-Reed et al, 2004a) or by other mechanisms related to genome/ replicative stress (Bartkova et al, 2005;Gorgoulis et al, 2005). Therefore, both the ultimate penetrance and the aggressiveness of the tumors observed in the T380A/ p53-heterozygous background may reflect both enhanced p53 LOH, and then subsequently a heightened sensitivity to other cyclin E-mediated oncogenic events, in effect a positive feedback loop.…”

“…Such deregulation correlates with accelerated entry into S-phase and prolongs S-phase without shortening the total cell cycle period (Resnitzky et al, 1994;Ohtsubo et al, 1995). Moreover, there is evidence emerging to support S-phase defects when cyclin E is expressed inappropriately during the cell cycle (Ekholm-Reed et al, 2004a). Therefore, it may be temporal deregulation of cyclin E rather than simple overexpression per se that contributes to cell cycle perturbation.…”

DNA repair, genome stability and cancer: a historical perspective

“…Concurrently, p53 and p21 were shown to prevent cell proliferation when Cyclin E/Cdk2 was over-expressed and that this operated through an ATM/ATR-dependent and p14ARF independent mechanism 69 . Cyclin E expression had been previously shown to cause chromosome instability 70 and later it was demonstrated to interfere with replication 71 . The scene was thus set: oncogene-induced proliferation of otherwise normal cells perturbed DNA replication mechanisms, producing measurable DNA damage and genome rearrangements and activating p53 -p21 via ATM/ATR-dependent mechanisms.…”