APC/CFzr/Cdh1 promotes cell cycle progression during the<i>Drosophila</i>endocycle

Narbonne-Reveau, Karine; Senger, Stefania; Pál, Margit; Herr, Anabel; Richardson, Helena E.; Asano, Maki; Deák, Péter; Lilly, Mary A.

doi:10.1242/dev.016295

Cited by 83 publications

(100 citation statements)

References 80 publications

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“…Kolpakas, S. Maqbool, and B. Calvi, unpubl.). Moreover, previous evidence suggested that the Dup inhibitor Geminin, and periodic inhibition of CDK2, is important for normal endocycle DNA replication (Hong et al 2007;Narbonne Reveau et al 2008;Zielke et al 2008). It is possible, however, that some aspects of the origin licensing mechanism differ between mitotic cycles and endocycles.…”

Section: Rereplication Is Distinct From the Normal Process Of Endoredmentioning

confidence: 99%

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

128

155

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Initiation of DNA replication at origins more than once per cell cycle results in rereplication and has been implicated in cancer. Here we use Drosophila to examine the checkpoint responses to rereplication in a developmental context. We find that increased Double-parked (Dup), the Drosophila ortholog of Cdt1, results in rereplication and DNA damage. In most cells, this rereplication triggers caspase activation and apoptotic cell death mediated by both p53-dependent and -independent pathways. Elevated Dup also caused DNA damage in endocycling cells, which switch to a G/S cycle during normal development, indicating that rereplication and the endocycling DNA reduplication program are distinct processes. Unexpectedly, however, endocycling cells do not apoptose regardless of tissue type. Our combined evidence suggests that endocycling apoptosis is repressed in part because proapoptotic gene promoters are silenced. Normal endocycling cells had DNA lesions near heterochromatin, which increased after rereplication, explaining why endocycling cells must constantly repress the genotoxic apoptotic response. Our results reveal a novel regulation of apoptosis in development and new insights into the little-understood endocycle. Similar mechanisms may operate during vertebrate development, with implications for cancer predisposition in certain tissues.[Keywords: DNA replication; DNA damage; endocycle; checkpoint; apoptosis] Supplemental material is available at http://www.genesdev.org. The timely duplication of the genome during S phase of every cell division cycle requires that DNA replication initiate from thousands of origins. If too few origins initiate, replication forks can collapse, resulting in DNA damage and incomplete replication of the genome. Initiation of DNA replication from origins more than once per cell cycle, however, results in "rereplication" and subsequent DNA damage (Arias and Walter 2007). In recent years, it has become increasingly apparent that problems with DNA replication are common in premalignant cells, with subsequent checkpoint defects leading to genome instability and cancer (Dutta 2007). It remains unclear, however, whether all cells in development are equivalent with respect to their regulation of DNA replication and checkpoint responses. Here, we use Drosophila to investigate the checkpoint responses to rereplication in a developmental context. Two important steps in the cell cycle regulation of DNA replication are the assembly and activation of a prereplicative complex (pre-RC) (Sivaprasad et al. 2006). The pre-RC assembles onto origins in early G1 and is subsequently activated in S phase. During pre-RC assembly, the hexameric origin recognition complex (ORC) serves as a scaffold for origin association of Cdc6 and Cdt1, which are both required to load the hexameric minichromosome maintenance complex (MCM), the replicative helicase (Randell et al. 2006;Sivaprasad et al. 2006). Once the MCM complex is tightly bound, the origins are considered to be "licensed" and competent to initiate replic...

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Section: Rereplication Is Distinct From the Normal Process Of Endoredmentioning

confidence: 99%

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Mehrotra¹,

Maqbool²,

Kolpakas³

et al. 2008

Genes Dev.

128

155

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“…At the molecular level, endoreduplication is likely achieved through elimination of the components needed to progress through mitosis (11). Predominant roles in this process are played by the anaphase-promoting complex/cyclosome (APC/C) activator genes, such as CDH1, FZR, and CCS52A, which have been found to promote endocycle onset and progression in human, Drososphila melanogaster, and Medicago truncatula cells, respectively (12)(13)(14)(15)(16)(17). The mechanisms controlling the transcriptional activity of these genes remain unclear, however.…”

mentioning

confidence: 99%

Atypical E2F activity restrains APC/C ^CCS52A2 function obligatory for endocycle onset

Lammens

Boudolf

Kheibarshekan

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

167

221

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The endocycle represents an alternative cell cycle that is activated in various developmental processes, including placental formation, Drosophila oogenesis, and leaf development. In endocycling cells, mitotic cell cycle exit is followed by successive doublings of the DNA content, resulting in polyploidy. The timing of endocycle onset is crucial for correct development, because polyploidization is linked with cessation of cell division and initiation of terminal differentiation. The anaphase-promoting complex/cyclosome (APC/C) activator genes CDH1, FZR, and CCS52 are known to promote endocycle onset in human, Drosophila, and Medicago species cells, respectively; however, the genetic pathways governing development-dependent APC/C CDH1/FZR/CCS52 activity remain unknown. We report that the atypical E2F transcription factor E2Fe/DEL1 controls the expression of the CDH1/FZR orthologous CCS52A2 gene from Arabidopsis thaliana. E2Fe/DEL1 misregulation resulted in untimely CCS52A2 transcription, affecting the timing of endocycle onset. Correspondingly, ectopic CCS52A2 expression drove cells into the endocycle prematurely. Dynamic simulation illustrated that E2Fe/DEL1 accounted for the onset of the endocycle by regulating the temporal expression of CCS52A2 during the cell cycle in a development-dependent manner. Analogously, the atypical mammalian E2F7 protein was associated with the promoter of the APC/C-activating CDH1 gene, indicating that the transcriptional control of APC/C activator genes by atypical E2Fs might be evolutionarily conserved.D uring the mitotic cell cycle, DNA that is duplicated during the S phase is divided at the M phase, so that each daughter cell produced has a genomic DNA content equal to that of its parents. In contrast, during the endoreduplication cycle, no cytokinesis occurs between rounds of DNA replication, resulting in successive doublings of the DNA ploidy level. This process occurs in a wide variety of cell types in arthropods and mammals and is particularly prominent in dicotyledonous plants (1), especially in species with a small genome and a short life cycle, in which repetitive DNA replication might support growth under conditions that require rapid development (2, 3).Mitotic cell cycle progression and endoreduplication are linked events. Premature or delayed exit from the cell division program results in an increased or decreased DNA ploidy, respectively (4-10). Therefore, the onset of endoreduplication must be controlled precisely. At the molecular level, endoreduplication is likely achieved through elimination of the components needed to progress through mitosis (11). Predominant roles in this process are played by the anaphase-promoting complex/cyclosome (APC/C) activator genes, such as CDH1, FZR, and CCS52A, which have been found to promote endocycle onset and progression in human, Drososphila melanogaster, and Medicago truncatula cells, respectively (12-17). The mechanisms controlling the transcriptional activity of these genes remain unclear, however.Over the years, it has beco...

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“…However, the entry into and the progression through endoreplication cycles do not necessarily have to be regulated by the same molecular mechanism. Nonetheless, it has recently been found that APC/C also controls progression through endoreplication cycles in Drosophila by targeting the replication inhibitor Geminin for degradation (16,17). However, Geminin is not present in all organisms and so, for instance, no Geminin ortholog could be thus far isolated from plants.…”

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confidence: 99%

CULLIN 4-RING FINGER-LIGASE plays a key role in the control of endoreplication cycles in Arabidopsis trichomes

Roodbarkelari

Bramsiepe

Weinl

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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One of the predominant cell-cycle programs found in mature tissues is endoreplication, also known as endoreduplication, that leads to cellular polyploidy. A key question for the understanding of endoreplication cycles is how oscillating levels of cyclindependent kinase activity are generated that control repeated rounds of DNA replication. The APC/C performs a pivotal function in the mitotic cell cycle by promoting anaphase and paving the road for a new round of DNA replication. However, using marker lines and plants in which APC/C components are knocked down, we show here that outgrowing and endoreplicating Arabidopsis leaf hairs display no or very little APC/C activity. Instead we find that RBX1-containing Cullin-RING E3 ubiquitin-Ligases (CRLs) are of central importance for the progression through endoreplication cycles; in particular, we have identified CULLIN4 as a major regulator of endoreplication in Arabidopsis trichomes. We have incorporated our findings into a bio-mathematical simulation presenting a robust two-step model of endoreplication control with one type of cyclindependent kinase inhibitor function for entry and a CRL-dependent oscillation of cyclin-dependent kinase activity via degradation of a second type of CDK inhibitor during endoreplication cycles.cell cycle | endoreduplication | CDK inhibitor | cell differentiation | protein degradation

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APC/CFzr/Cdh1 promotes cell cycle progression during theDrosophilaendocycle

Cited by 83 publications

References 80 publications

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Atypical E2F activity restrains APC/C ^CCS52A2 function obligatory for endocycle onset

CULLIN 4-RING FINGER-LIGASE plays a key role in the control of endoreplication cycles in Arabidopsis trichomes

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APC/CFzr/Cdh1 promotes cell cycle progression during theDrosophilaendocycle

Cited by 83 publications

References 80 publications

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Endocycling cells do not apoptose in response to DNA rereplication genotoxic stress

Atypical E2F activity restrains APC/C CCS52A2 function obligatory for endocycle onset

CULLIN 4-RING FINGER-LIGASE plays a key role in the control of endoreplication cycles in Arabidopsis trichomes

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Atypical E2F activity restrains APC/C ^CCS52A2 function obligatory for endocycle onset