Rbf1-independent termination of E2f1-target gene expression during early<i>Drosophila</i>embryogenesis

Shibutani, Shusaku; Swanhart, Lisa M.; Duronio, Robert J.

doi:10.1242/dev.02738

Cited by 26 publications

(34 citation statements)

References 79 publications

(102 reference statements)

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“…Moreover, it has been recently demonstrated that DNA replication is necessary for E2F1 destruction (Shibutani et al 2007). Hence, E2F1 stabilization caused by overexpression of HA-Rca1 or CycE may be due to the failure to undergo DNA replication, which normally initiates E2F1 turnover.…”

Section: Genes and Development 1695mentioning

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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Section: Genes and Development 1695mentioning

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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“…In Drosophila , the first 13 embryonic cell cycles are synchronous, consisting of only S and M phases. G2 appears in cell cycle 14 and G1 in cell cycle 17 (Foe 1989; Edgar and O’Farrell 1990; Shibutani et al 2007). Endoreplication (in which mitosis is not followed by cytokinesis) is another variant common in many larval and adult tissues (Spradling and Orr-Weaver 1987).…”

mentioning

confidence: 99%

Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of theDrosophilaRetinoblastoma Protein

Acharya

Nègre

Johnston

et al. 2012

G3 Genes|Genomes|Genetics

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The retinoblastoma (RB) tumor suppressor protein is a transcriptional cofactor with essential roles in cell cycle and development. Physical and functional targets of RB and its paralogs p107/p130 have been studied largely in cultured cells, but the full biological context of this family of proteins’ activities will likely be revealed only in whole organismal studies. To identify direct targets of the major Drosophila RB counterpart in a developmental context, we carried out ChIP-Seq analysis of Rbf1 in the embryo. The association of the protein with promoters is developmentally controlled; early promoter access is globally inhibited, whereas later in development Rbf1 is found to associate with promoter-proximal regions of approximately 2000 genes. In addition to conserved cell-cycle–related genes, a wholly unexpected finding was that Rbf1 targets many components of the insulin, Hippo, JAK/STAT, Notch, and other conserved signaling pathways. Rbf1 may thus directly affect output of these essential growth-control and differentiation pathways by regulation of expression of receptors, kinases and downstream effectors. Rbf1 was also found to target multiple levels of its own regulatory hierarchy. Bioinformatic analysis indicates that different classes of genes exhibit distinct constellations of motifs associated with the Rbf1-bound regions, suggesting that the context of Rbf1 recruitment may vary within the Rbf1 regulon. Many of these targeted genes are bound by Rbf1 homologs in human cells, indicating that a conserved role of RB proteins may be to adjust the set point of interlinked signaling networks essential for growth and development.

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“…Previous work from the Duronio lab has shown that E2f1 is rapidly destabilized as cells enter S phase and re-accumulates later during interphase in the embryo. 12 This is similar to the case of Cdt1, a protein that loads MCM replication factors onto DNA and is essential for S phase. Previous work on Cdt degradation showed that PCNA binds a PIP (PCNA interacting) motif in the amino-terminus of Cdt1, and this interaction is thought to recruit a Cul4 E3 ubiquitin ligase that targets Cdt1for degradation.…”

Section: Cell Cycle Regulationmentioning

confidence: 66%

Cell Cycle Regulation

Garcia¹,

Su²

2008

Fly

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

Cited by 26 publications

References 79 publications

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

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

Evidence for Autoregulation and Cell Signaling Pathway Regulation From Genome-Wide Binding of theDrosophilaRetinoblastoma Protein

Cell Cycle Regulation

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