Cyclin E-dependent localization of MCM5 regulates centrosome duplication

Ferguson, Rebecca L.; Maller, James L.

doi:10.1242/jcs.034702

Cited by 46 publications

(63 citation statements)

References 57 publications

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“…Cyclin E binds and recruits MCM5 (an MCM complex component) to the centrosome. 49 Subsequently, rising Cyclin A levels induce firing of DNA replication origins, degradation of the majority of ORC1, and translocation of the remainder of ORC1 and MCM5 to the cytosol and centrosome. [50][51][52] ORC1 removal from the nucleus prevents untimely DNA replication relicensure.…”

Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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Nearly a century ago, cell biologists postulated that the chromosomal aberrations blighting cancer cells might be caused by a mysterious organelle-the centrosome-that had only just been discovered. For years, however, this enigmatic structure was neglected in oncologic investigations and has only recently reemerged as a key suspect in tumorigenesis. A majority of cancer cells, unlike healthy cells, possess an amplified centrosome complement, which they manage to coalesce neatly at two spindle poles during mitosis. This clustering mechanism permits the cell to form a pseudo-bipolar mitotic spindle for segregation of sister chromatids. On rare occasions this mechanism fails, resulting in declustered centrosomes and the assembly of a multipolar spindle. Spindle multipolarity consigns the cell to an almost certain fate of mitotic arrest or death. The catastrophic nature of multipolarity has attracted efforts to develop drugs that can induce declustering in cancer cells. Such chemotherapeutics would theoretically spare healthy cells, whose normal centrosome complement should preclude multipolar spindle formation. In search of the 'Holy Grail' of nontoxic, cancer cell-selective, and superiorly efficacious chemotherapy, research is underway to elucidate the underpinnings of centrosome clustering mechanisms. Here, we detail the progress made towards that end, highlighting seminal work and suggesting directions for future research, aimed at demystifying this riddling cellular tactic and exploiting it for chemotherapeutic purposes. We also propose a model to highlight the integral role of microtubule dynamicity and the delicate balance of forces on which cancer cells rely for effective centrosome clustering. Finally, we provide insights regarding how perturbation of this balance may pave an inroad for inducing lethal centrosome dispersal and death selectively in cancer cells.

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Section: Excess Baggage: How Cancer Cells Acquire Extra Centrosomesmentioning

confidence: 99%

Let's huddle to prevent a muddle: centrosome declustering as an attractive anticancer strategy

2012

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“…Besides, cyclin E interacts directly with MCM5 through its CLS domain and recruits MCM5 to the centrosomes. Over-expressing MCM5 or the domain of MCM5 which is responsible for cyclin E interaction inhibits the centrosome re-duplication of S phase arrested cells (Ferguson and Maller 2008). All these data indicate that CDK2/cyclin E functions in centrosome duplication.…”

Section: The Roles Of the Key Regulators Of The Dna Replication Licenmentioning

confidence: 85%

“…All these data indicate that CDK2/cyclin E functions in centrosome duplication. The possible mechanism will be that, at the late G1 phase, CDK2/cyclin E phosphorylates and releases its substrates including B23 from the unduplicated centrosome to initiate centrosome duplication; during the progress of the centrosome duplication in the S phase, CDK2/cyclin E activity is not needed and suppressed by another series of proteins such as ORC1 and MCM5 as reported (Hemerly et al 2009, Ferguson andMaller 2008). So far the reported inhibitor proteins for CDK2/cyclin E are mostly DNA replication licensing proteins.…”

Section: The Roles Of the Key Regulators Of The Dna Replication Licenmentioning

confidence: 90%

“…Simultaneous depletion of cyclin E and ORC1 inhibits the reduplication of centrioles caused by ORC1 depletion (Hemerly et al 2009). Moreover, MCM5 also localizes to centrosomes depending on its interaction with CLS domain of cyclin E and prevents centrosome over-duplication in S phase-arrested cells by interacting with cyclin E (Ferguson and Maller 2008). Geminin is a DNA replication licensing inhibitor.…”

Section: The Roles Of the Dna Replication Licensing System Proteins Imentioning

confidence: 99%

“…The coiled-coil domain of geminin is responsible for its centrosome localization and interaction with Arp1 and is required for the inhibition of centrosome reduplication (Lu et al 2009). Although a number of reports (Hemerly et al 2009, Ferguson and Maller 2008, Tachibana et al 2005, Lu et al 2009) indicate that the same partners in DNA licensing play roles in centrosome duplication, their functional cooperation in centrosome duplication and preventing re-duplication are not yet described.…”

Section: The Roles Of the Dna Replication Licensing System Proteins Imentioning

confidence: 99%

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