Levels of the origin-binding protein Double parked and its inhibitor Geminin increase in response to replication stress

May, Noah R.; Thomer, Marguerite; Murnen, Katherine; Calvi, Brian R.

doi:10.1242/jcs.02534

Cited by 23 publications

(27 citation statements)

References 94 publications

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“…In vertebrates, Cdt1 destruction is mediated by two independent and apparently redundant mechanisms: direct Cdk2 phosphorylation that targets Cdt1 to SCF SKP2 , and binding of PCNA to the Cdt1/Dup amino-terminus that targets Cdt1 to Cul4 DDB1 Nishitani et al, 2006;Senga et al, 2006). This latter result is consistent with a recent study indicating that Drosophila Dup hyperaccumulates in cells where DNA synthesis is attenuated (May et al, 2005). Thus, more than one E3 ubiquitin ligase may participate in E2f1 destruction (Ohta and Xiong, 2001).…”

Section: Mechanisms Of Cell Cycle-regulated E2f1 Destructionsupporting

confidence: 88%

Rbf1-independent termination of E2f1-target gene expression during earlyDrosophilaembryogenesis

2007

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The initiation and maintenance of G1 cell cycle arrest is a key feature of animal development. In the Drosophila ectoderm, G1 arrest first appears during the seventeenth embryonic cell cycle. The initiation of G1 17 arrest requires the developmentally-induced expression of Dacapo, a p27-like Cyclin E-Cdk2 inhibitor. The maintenance of G1 17 arrest requires Rbf1-dependent repression of E2f1-regulated replication factor genes, which are expressed continuously during cycles 1-16 when S phase immediately follows mitosis. The mechanisms that trigger Rbf1 repressor function and mediate G1 17 maintenance are unknown. Here we show that the initial downregulation of expression of the E2f1-target gene RnrS, which occurs during cycles 15 and 16 prior to entry into G1 17 , does not require Rbf1 or p27Dap . This suggests a mechanism for Rbf1-independent control of E2f1 during early development. We show that E2f1 protein is destroyed in a cell cycle-dependent manner during S phase of cycles 15 and 16. E2f1 is destroyed during early S phase, and requires ongoing DNA replication. E2f1 protein reaccumulates in epidermal cells arrested in G1 17 , and in these cells the induction of p27Dap activates Rbf1 to repress E2f1-target genes to maintain a stable G1 arrest.

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Section: Mechanisms Of Cell Cycle-regulated E2f1 Destructionsupporting

confidence: 88%

Rbf1-independent termination of E2f1-target gene expression during earlyDrosophilaembryogenesis

2007

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“…This allows Cyclin E/cdk2 to phosphorylate Cdt1/Dup, leading to its degradation. 16 This model also fits well with the observations that fluctuation of CyclinE/ cdk2 activities is required for progression of endocycles 17,18 and that constitutive Cyclin E expression first induces and then inhibits endoreplication. [19][20][21] It appears as if endocycling cells single-mindedly pursue the mission of polyploidy: they eliminate mitosis by shutting down mitotic cyclin activities, 22,23 eliminate cell cycle arrest by shutting down checkpoint pathways to go through multi-round of replication with under-replicated heterochromatin (reviewed in refs.…”

supporting

confidence: 82%

Endoreplication: The advantage to initiating DNA replication without the ORC?

Asano

2009

Fly

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“…CycE-Cdk2 then enhances its own activity by inhibiting the E2F1 repressor Rbf (Du et al 1996) resulting in a sharp peak of Cdk2 activity, which eventually triggers S-phase entry. The onset of DNA replication in turn initiates a negative feedback loop that downregulates E2F1 activity and simultaneously triggers dup/ Cdt1 degradation (May et al 2005). The short half-live of CycE mRNA and protein would then suffice to cause a drop in CycE-Cdk2 activity after completion of DNA replication (Fig.…”

Section: Discussionmentioning

confidence: 99%

The anaphase-promoting complex/cyclosome (APC/C) is required for rereplication control in endoreplication cycles

Zielke¹,

Querings²,

Rottig

et al. 2008

Genes Dev.

111

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Endoreplicating cells undergo multiple rounds of DNA replication leading to polyploidy or polyteny. Oscillation of Cyclin E (CycE)-dependent kinase activity is the main driving force in Drosophila endocycles. High levels of CycE-Cdk2 activity trigger S phase, while down-regulation of CycE-Cdk2 activity is crucial to allow licensing of replication origins. In mitotic cells relicensing in S phase is prevented by Geminin. Here we show that Geminin protein oscillates in endoreplicating salivary glands of Drosophila. Geminin levels are high in S phase, but drop once DNA replication has been completed. DNA licensing is coupled to mitosis through the action of the anaphase-promoting complex/cyclosome (APC/C). We demonstrate that, even though endoreplicating cells never enter mitosis, APC/C activity is required in endoreplicating cells to mediate Geminin oscillation. Down-regulation of APC/C activity results in stabilization of Geminin protein and blocks endocycle progression. Geminin is only abundant in cells with high CycE-Cdk2 activity, suggesting that APC/C-Fzr activity is periodically inhibited by CycE-Cdk2, to prevent relicensing in S-phase cells.[Keywords: Anaphase-promoting complex; cell cycle; DNA licensing; Drosophila; endoreplication] Supplemental material is available at http://www.genesdev.org. The precise duplication of the genome is crucial for the survival of any organism. In multicellular organisms genome instability potentially gives rise to cancer and thus compromises the life of the whole organism. To maintain the integrity of the genome, DNA replication, and mitosis must be coordinated during cell division cycles so that DNA replication occurs only once per cycle and mitosis only after complete duplication of the genome. To avoid rereplication events, a network of proteins ensures that cells acquire the license for DNA replication only in a specific phase of the cell cycle. DNA licensing involves the formation of prereplication complexes (pre-RC), which can only assemble during late mitosis and G1 (for review, see Bell and Dutta 2002;Blow and Dutta 2005). Pre-RC assembly on replication origins involves a variety of conserved components including the ORC1-6 complex, Cdc6, Cdt1/Double-parked, and the MCM2-7 helicase. Once MCM2-7 proteins are loaded onto the DNA, licensing is completed and the replication origins are ready for firing (for review, see Bell and Dutta 2002;Blow and Dutta 2005).Several mechanisms ensure that replication origins are fired only once during a cell cycle (for review, see Machida et al. 2005). Of particular importance is the temporal separation of pre-RC formation and origin firing. Pre-RC assembly occurs only in G1 because it depends on low Cdk activity while high Cdk activity is required for origin firing. The increase in Cdk activity at the G1-S transition does not only trigger origin firing, but at the same time also results in phosphorylation of several pre-RC components (ORC, Cdc6, Cdt1,. These modifications are thought to prevent reassembly of these components into pre-R...

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Levels of the origin-binding protein Double parked and its inhibitor Geminin increase in response to replication stress

Cited by 23 publications

References 94 publications

Rbf1-independent termination of E2f1-target gene expression during earlyDrosophilaembryogenesis

Rbf1-independent termination of E2f1-target gene expression during earlyDrosophilaembryogenesis

Endoreplication: The advantage to initiating DNA replication without the ORC?

The anaphase-promoting complex/cyclosome (APC/C) is required for rereplication control in endoreplication cycles

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