Identification of the critical replication targets of CDK reveals direct regulation of replication initiation factors by the embryo polarity machinery in C. elegans

Autor: Richard Butler, Anna Klucnika, Philip Zegerman, Manuela R. Kieninger, Vincent Gaggioli
Přispěvatelé: Kieninger, Manuela R [0000-0002-1841-0273], Klucnika, Anna [0000-0001-6102-7141], Butler, Richard [0000-0002-3885-1332], Zegerman, Philip [0000-0002-5707-1083], Apollo - University of Cambridge Repository, Kieninger, Manuela R. [0000-0002-1841-0273]
Rok vydání: 2020
Předmět:
Cancer Research
Cyclin E
Nematoda
Synthesis Phase
QH426-470
Biochemistry
RNA interference
0302 clinical medicine
Cell Cycle and Cell Division
Post-Translational Modification
Phosphorylation
Protein Kinase C
Genetics (clinical)
Caenorhabditis elegans
Cyclin
0303 health sciences
biology
Eukaryota
Cell Polarity
Animal Models
Cell cycle
Cyclin-Dependent Kinases
Cell biology
Nucleic acids
Experimental Organism Systems
Genetic interference
Cell Processes
Epigenetics
Research Article
DNA Replication
Cell Physiology
DNA replication initiation
03 medical and health sciences
Model Organisms
Cyclin-dependent kinase
Cyclins
Genetics
Animals
Caenorhabditis elegans Proteins
Molecular Biology
Ecology
Evolution
Behavior and Systematics
Body Patterning
030304 developmental biology
Biology and life sciences
Organisms
DNA replication
Proteins
Cell Biology
DNA
biology.organism_classification
Invertebrates
Research and analysis methods
Replication Initiation
Mutation
Animal Studies
Caenorhabditis
biology.protein
RNA
Gene expression
Zoology
030217 neurology & neurosurgery
Zdroj: PLoS Genetics
PLoS Genetics, Vol 16, Iss 12, p e1008948 (2020)
DOI: 10.17863/cam.62749
Popis: During metazoan development, the cell cycle is remodelled to coordinate proliferation with differentiation. Developmental cues cause dramatic changes in the number and timing of replication initiation events, but the mechanisms and physiological importance of such changes are poorly understood. Cyclin-dependent kinases (CDKs) are important for regulating S-phase length in many metazoa, and here we show in the nematode Caenorhabditis elegans that an essential function of CDKs during early embryogenesis is to regulate the interactions between three replication initiation factors SLD-3, SLD-2 and MUS-101 (Dpb11/TopBP1). Mutations that bypass the requirement for CDKs to generate interactions between these factors is partly sufficient for viability in the absence of Cyclin E, demonstrating that this is a critical embryonic function of this Cyclin. Both SLD-2 and SLD-3 are asymmetrically localised in the early embryo and the levels of these proteins inversely correlate with S-phase length. We also show that SLD-2 asymmetry is determined by direct interaction with the polarity protein PKC-3. This study explains an essential function of CDKs for replication initiation in a metazoan and provides the first direct molecular mechanism through which polarization of the embryo is coordinated with DNA replication initiation factors.
Author summary How and when a cell divides changes as the cell assumes different fates. How these changes in cell division are brought about are poorly understood, but are critical to ensure that cells do not over-proliferate leading to cancer. The nematode C. elegans is an excellent system to study the role of cell cycle changes during animal development. Here we show that two factors SLD-2 and SLD-3 are critical to control the decision to begin genome duplication. We show that these factors are differently distributed to different cell lineages in the early embryo, which may be a key event in determining the cell cycle rate in these cells. For the first time we show that, PKC-3, a key component of the machinery that determines the front (anterior) from the back (posterior) of the embryo directly controls SLD-2 distribution, which might explain how the polarisation of the embryo causes changes in the proliferation of different cell lineages. As PKC-3 is frequently mutated in human cancers, how this factor controls cell proliferation may be important to understand tumour progression.
Databáze: OpenAIRE
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