Header

UZH-Logo

Maintenance Infos

Control of Drosophila endocycles by E2F and CRL4(CDT2)


Zielke, N; Kim, K J; Tran, V; Shibutani, S T; Bravo, M J; Nagarajan, S; van Straaten, M; Woods, B; von Dassow, G; Rottig, C; Lehner, C F; Grewal, S S; Duronio, R J; Edgar, B A (2011). Control of Drosophila endocycles by E2F and CRL4(CDT2). Nature, 480(7375):123-144.

Abstract

Endocycles are variant cell cycles comprised of DNA synthesis (S)- and gap (G)-phases but lacking mitosis1,2. Such cycles facilitate post-mitotic growth in many invertebrate and plant cells, and are so ubiquitous that they may account for up to half the world’s biomass3,4. DNA replication in endocycling Drosophila cells is triggered by cyclin E/cyclin dependent kinase 2 (CYCE/CDK2), but this kinase must be inactivated during each G-phase to allow the assembly of pre-Replication Complexes (preRCs) for the next S-phase5,6. How CYCE/CDK2 is periodically silenced to allow re- replication has not been established. Here, using genetic tests in parallel with computational modelling, we show that the endocycles of Drosophila are driven by a molecular oscillator in which the E2F1 transcription factor promotes CycE expression and S-phase initiation, S-phase then activates the CRL4CDT2 ubiquitin ligase, and this in turn mediates the destruction of E2F1 (ref. 7). We pro- pose that it is the transient loss of E2F1 during S phases that creates the window of low Cdk activity required for preRC formation. In support of this model overexpressed E2F1 accelerated endocycling, whereas a stabilized variant of E2F1 blocked endocycling by de- regulating target genes, including CycE, as well as Cdk1 and mitotic cyclins. Moreover, we find that altering cell growth by changing nutrition or target of rapamycin (TOR) signalling impacts E2F1 translation, thereby making endocycle progression growth- dependent. Many of the regulatory interactions essential to this novel cell cycle oscillator are conserved in animals and plants1,2,8, indicating that elements of this mechanism act in most growth- dependent cell cycles.

Abstract

Endocycles are variant cell cycles comprised of DNA synthesis (S)- and gap (G)-phases but lacking mitosis1,2. Such cycles facilitate post-mitotic growth in many invertebrate and plant cells, and are so ubiquitous that they may account for up to half the world’s biomass3,4. DNA replication in endocycling Drosophila cells is triggered by cyclin E/cyclin dependent kinase 2 (CYCE/CDK2), but this kinase must be inactivated during each G-phase to allow the assembly of pre-Replication Complexes (preRCs) for the next S-phase5,6. How CYCE/CDK2 is periodically silenced to allow re- replication has not been established. Here, using genetic tests in parallel with computational modelling, we show that the endocycles of Drosophila are driven by a molecular oscillator in which the E2F1 transcription factor promotes CycE expression and S-phase initiation, S-phase then activates the CRL4CDT2 ubiquitin ligase, and this in turn mediates the destruction of E2F1 (ref. 7). We pro- pose that it is the transient loss of E2F1 during S phases that creates the window of low Cdk activity required for preRC formation. In support of this model overexpressed E2F1 accelerated endocycling, whereas a stabilized variant of E2F1 blocked endocycling by de- regulating target genes, including CycE, as well as Cdk1 and mitotic cyclins. Moreover, we find that altering cell growth by changing nutrition or target of rapamycin (TOR) signalling impacts E2F1 translation, thereby making endocycle progression growth- dependent. Many of the regulatory interactions essential to this novel cell cycle oscillator are conserved in animals and plants1,2,8, indicating that elements of this mechanism act in most growth- dependent cell cycles.

Statistics

Citations

50 citations in Web of Science®
53 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

145 downloads since deposited on 09 Jan 2012
23 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:07 Faculty of Science > Institute of Molecular Life Sciences
Special Collections > SystemsX.ch
Special Collections > SystemsX.ch > Research, Technology and Development Projects > WingX
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:1 December 2011
Deposited On:09 Jan 2012 12:58
Last Modified:21 Nov 2017 15:43
Publisher:Nature Publishing Group
ISSN:0028-0836
Free access at:PubMed ID. An embargo period may apply.
Publisher DOI:https://doi.org/10.1038/nature10579
PubMed ID:22037307

Download

Download PDF  'Control of Drosophila endocycles by E2F and CRL4(CDT2)'.
Preview
Content: Accepted Version
Filetype: PDF
Size: 4MB
View at publisher