New insights into cell cycle control from the Drosophila endocycle

Lilly, Mary A.; Duronio, Robert J.

doi:10.1038/sj.onc.1208610

Cited by 134 publications

(128 citation statements)

References 104 publications

(117 reference statements)

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“…The endocycle is phylogenetically widespread, and a number of different cell types enter an endocycle program during vertebrate development (Edgar and Orr-Weaver 2001;Lilly and Duronio 2005). Interestingly, it was previously shown that the giant trophoblast cells of the rodent placenta are resistant to apoptosis, but it is unclear if the mechanism is similar to the one we described here (Soloveva and Linzer 2004).…”

Section: Apoptotic Repression Cell Proliferation and Cancermentioning

confidence: 55%

“…A current challenge, therefore, is to understand how cell cycle regulation and genome maintenance are integrated with development. For example, in several tissues in Drosophila, developmental signals induce certain cells to enter a specialized endocycle that is comprised of alternating G and S phases without mitosis, which results in genome polyploidization (Edgar and Orr-Weaver 2001;Lilly and Duronio 2005). Endocycles are controlled by the oscillating activity of the CDK complex, Cyclin E/CDK2, and most of the genome is duplicated exactly once during each endocycle S phase, although some heterochromatic sequences are not duplicated (Gall et al 1971;Sauer et al 1995;Lilly and Spradling 1996;Calvi et al 1998;Parisi et al 2003).…”

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confidence: 99%

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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: Apoptotic Repression Cell Proliferation and Cancermentioning

confidence: 55%

mentioning

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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“…In Drosophila, which is often used as a model organism for studying the mammalian cell cycle, endocycle (37), ovary, and salivary gland cells as they enter the endocycle and become polyploid. In this state, many E2F-regulated and mitosis-associated transcripts are inhibited (38). Genes correctly predicted in ovary and salivary gland negative sets include nuclear mitotic apparatus protein 1 (NUMA1), HLA-B associated transcript 3 (BAT3), kelch domain containing 3 (KLHDC3), and DEAH box polypeptide 30 (DHX30).…”

Section: Resultsmentioning

confidence: 99%

DNA motifs in human and mouse proximal promoters predict tissue-specific expression

Smith

Sumazin

Xuan

et al. 2006

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

118

126

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Comprehensive identification of cis-regulatory elements is necessary for accurately reconstructing gene regulatory networks. We studied proximal promoters of human and mouse genes with differential expression across 56 terminally differentiated tissues. Using in silico techniques to discover, evaluate, and model interactions among sequence elements, we systematically identified regulatory modules that distinguish elevated from inhibited expression in the corresponding transcripts. We used these putative regulatory modules to construct a single predictive model for each of the 56 tissues. These predictors distinguish tissue-specific elevated from inhibited expression with statistical significance in 80% of the tissues (45 of 56). The predictors also reveal synergy between cis-regulatory modules and explain large-scale tissuespecific differential expression. For testis and liver, the predictors include computationally predicted motifs. For most other tissues, the predictors reveal synergy between experimentally verified motifs and indicate genes that are regulated by similar tissuespecific machinery. The identification in proximal promoters of cis-regulatory modules with tissue-specific activity lays the groundwork for complete characterization and deciphering of cis-regulatory DNA code in mammalian genomes.cis-regulatory modules ͉ transcription factor binding A major first step toward comprehensively understanding the differential control of gene expression in specific tissues and developmental stages is mapping the functional cis-regulatory modules (CRMs) (1) responsible for transcription regulation. CRMs are autonomous units of transcription programs encoded in DNA (2-4) and are largely composed of transcription factorbinding sites (TFBSs). Identification and categorization of the entire repertoire of TFBSs are among the greatest challenges in systems biology (5-7). Although CRM identification in lower eukaryotes, such as various yeast species, has been progressing rapidly (8, 9), similar efforts in vertebrates have proven to be especially difficult due to the genomic and regulatory complexity of the higher organisms (10). CRMs in vertebrate regulatory regions not only control transcription during the life of individual cells but also must orchestrate cellular communication during tissue differentiation, morphogenesis, and body-part formation (11), as well as maintain specific patterns of transcription in terminally differentiated tissues (12).Recent work to predict expression using cis-regulatory elements includes studies on yeast (6,9,13,14), identification of target genes and binding sites for specific transcription factors (15, 16), and an evaluation of the effect of TFBS quality (17) on target regulation. Bussemaker et al. (13) and Conlon et al. (14) used linear regression to fit the count of predicted cis-regulatory elements (13) or the sum of the likelihood ratios of all potential cis-regulatory elements (14) to expression intensity. Beer and Tavazoie (6) used cis-regulatory elements in promoters to s...

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“…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)(13)(14)(15)(16)(17).…”

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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New insights into cell cycle control from the Drosophila endocycle

Cited by 134 publications

References 104 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

DNA motifs in human and mouse proximal promoters predict tissue-specific expression

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

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New insights into cell cycle control from the Drosophila endocycle

Cited by 134 publications

References 104 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

DNA motifs in human and mouse proximal promoters predict tissue-specific expression

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

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