title: APC/CFzr/Cdh1 promotes cell cycle progression during the Drosophila endocycle.
abstract: The endocycle is a commonly observed variant cell cycle in which cells undergo repeated rounds of DNA replication with no intervening mitosis. How the cell cycle machinery is modified to transform a mitotic cycle into endocycle has long been a matter of interest. In both plants and animals, the transition from the mitotic cycle to the endocycle requires Fzr/Cdh1, a positive regulator of the Anaphase-Promoting Complex/Cyclosome (APC/C). However, because many of its targets are transcriptionally downregulated upon entry into the endocycle, it remains unclear whether the APC/C functions beyond the mitotic/endocycle boundary. Here, we report that APC/C Fzr/Cdh1 activity is required to promote the G/S oscillation of the Drosophila endocycle. We demonstrate that compromising APC/C activity, after cells have entered the endocycle, inhibits DNA replication and results in the accumulation of multiple APC/C targets, including the mitotic cyclins and Geminin. Notably, our data suggest that the activity of APC/C Fzr/Cdh1 during the endocycle is not continuous but is cyclic, as demonstrated by the APC/C-dependent oscillation of the pre-replication complex component Orc1. Taken together, our data suggest a model in which the cyclic activity of APC/C Fzr/Cdh1 during the Drosophila endocycle is driven by the periodic inhibition of Fzr/Cdh1 by Cyclin E/Cdk2. We propose that, as is observed in mitotic cycles, during endocycles, APC/C Fzr/Cdh1 functions to reduce the levels of the mitotic cyclins and Geminin in order to facilitate the relicensing of DNA replication origins and cell cycle progression.
authors.affiliation: Cell Biology and Metabolism Program, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Karine
authors.initials: K
authors.lastname: Narbonne-Reveau
authors.forename: Stefania
authors.initials: S
authors.lastname: Senger
authors.forename: Margit
authors.initials: M
authors.lastname: Pal
authors.forename: Anabel
authors.initials: A
authors.lastname: Herr
authors.forename: Helena E
authors.initials: HE
authors.lastname: Richardson
authors.forename: Maki
authors.initials: M
authors.lastname: Asano
authors.forename: Peter
authors.initials: P
authors.lastname: Deak
authors.forename: Mary A
authors.initials: MA
authors.lastname: Lilly
mesh_terms: D064173:Anaphase-Promoting Complex-Cyclosome; D000818:Animals; D030801:Animals, Genetically Modified; D064200:Cdh1 Proteins; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism*; D004261:DNA Replication; D015536:Down-Regulation; D004330:Drosophila / Q000166:cytology* / Q000235:genetics / Q000378:metabolism*; D029721:Drosophila Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D017344:Genes, Insect; D008938:Mitosis; D008954:Models, Biological; D051738:Origin Recognition Complex / Q000235:genetics / Q000378:metabolism; D043743:Ubiquitin-Protein Ligase Complexes / Q000235:genetics / Q000378:metabolism*
chemical_list: C118001:APC protein, Drosophila; D064200:Cdh1 Proteins; D018797:Cell Cycle Proteins; D003598:Cytoskeletal Proteins; D029721:Drosophila Proteins; C497213:Orc1 protein, Drosophila; D051738:Origin Recognition Complex; C577674:fzr protein, Drosophila; D043743:Ubiquitin-Protein Ligase Complexes; D064173:Anaphase-Promoting Complex-Cyclosome