title: A general G1/S-phase cell-cycle control module in the flowering plant Arabidopsis thaliana.
abstract: The decision to replicate its DNA is of crucial importance for every cell and, in many organisms, is decisive for the progression through the entire cell cycle. A comparison of animals versus yeast has shown that, although most of the involved cell-cycle regulators are divergent in both clades, they fulfill a similar role and the overall network topology of G1/S regulation is highly conserved. Using germline development as a model system, we identified a regulatory cascade controlling entry into S phase in the flowering plant Arabidopsis thaliana, which, as a member of the Plantae supergroup, is phylogenetically only distantly related to Opisthokonts such as yeast and animals. This module comprises the Arabidopsis homologs of the animal transcription factor E2F, the plant homolog of the animal transcriptional repressor Retinoblastoma (Rb)-related 1 (RBR1), the plant-specific F-box protein F-BOX-LIKE 17 (FBL17), the plant specific cyclin-dependent kinase (CDK) inhibitors KRPs, as well as CDKA;1, the plant homolog of the yeast and animal Cdc2⁺/Cdk1 kinases. Our data show that the principle of a double negative wiring of Rb proteins is highly conserved, likely representing a universal mechanism in eukaryotic cell-cycle control. However, this negative feedback of Rb proteins is differently implemented in plants as it is brought about through a quadruple negative regulation centered around the F-box protein FBL17 that mediates the degradation of CDK inhibitors but is itself directly repressed by Rb. Biomathematical simulations and subsequent experimental confirmation of computational predictions revealed that this regulatory circuit can give rise to hysteresis highlighting the here identified dosage sensitivity of CDK inhibitors in this network.
authors.affiliation: Department of Molecular Mechanisms of Phenotypic Plasticity, Institut de Biologie Moléculaire des Plantes, Centre National de la Recherche Scientifique, Université de Strasbourg, Strasbourg, France.
authors.forename: Xin'Ai
authors.initials: X
authors.lastname: Zhao
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Harashima
authors.forename: Nico
authors.initials: N
authors.lastname: Dissmeyer
authors.forename: Stefan
authors.initials: S
authors.lastname: Pusch
authors.forename: Annika K
authors.initials: AK
authors.lastname: Weimer
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramsiepe
authors.forename: Daniel
authors.initials: D
authors.lastname: Bouyer
authors.forename: Svenja
authors.initials: S
authors.lastname: Rademacher
authors.forename: Moritz K
authors.initials: MK
authors.lastname: Nowack
authors.forename: Bela
authors.initials: B
authors.lastname: Novak
authors.forename: Stefanie
authors.initials: S
authors.lastname: Sprunck
authors.forename: Arp
authors.initials: A
authors.lastname: Schnittger
mesh_terms: D000818:Animals; D017360:Arabidopsis / Q000235:genetics / Q000378:metabolism*; D029681:Arabidopsis Proteins / Q000235:genetics / Q000378:metabolism; D016203:CDC2 Protein Kinase / Q000235:genetics / Q000378:metabolism; D003198:Computer Simulation; D050756:Cyclin-Dependent Kinase Inhibitor Proteins / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases / Q000235:genetics / Q000378:metabolism; D050704:E2F4 Transcription Factor / Q000235:genetics / Q000378:metabolism; D044783:F-Box Proteins / Q000235:genetics / Q000378:metabolism; D035264:Flowers / Q000235:genetics / Q000378:metabolism*; D016193:G1 Phase / Q000235:genetics*; D018506:Gene Expression Regulation, Plant; D053263:Gene Regulatory Networks; D008954:Models, Biological; D016196:S Phase / Q000235:genetics*; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: C532796:AT3G54650 protein, Arabidopsis; D029681:Arabidopsis Proteins; D050756:Cyclin-Dependent Kinase Inhibitor Proteins; D050704:E2F4 Transcription Factor; D044783:F-Box Proteins; C487568:RBR1 protein, Arabidopsis; D016203:CDC2 Protein Kinase; C434472:CDKA1 protein, Arabidopsis; D018844:Cyclin-Dependent Kinases