title: Down-regulation of tricarboxylic acid (TCA) cycle genes blocks progression through the first mitotic division in Caenorhabditis elegans embryos.
abstract: The cell cycle is a highly regulated process that enables the accurate transmission of chromosomes to daughter cells. Here we uncover a previously unknown link between the tricarboxylic acid (TCA) cycle and cell cycle progression in the Caenorhabditis elegans early embryo. We found that down-regulation of TCA cycle components, including citrate synthase, malate dehydrogenase, and aconitase, resulted in a one-cell stage arrest before entry into mitosis: pronuclear meeting occurred normally, but nuclear envelope breakdown, centrosome separation, and chromosome condensation did not take place. Mitotic entry is controlled by the cyclin B-cyclin-dependent kinase 1 (Cdk1) complex, and the inhibitory phosphorylation of Cdk1 must be removed in order for the complex to be active. We found that following down-regulation of the TCA cycle, cyclin B levels were normal but CDK-1 remained inhibitory-phosphorylated in one-cell stage-arrested embryos, indicative of a G2-like arrest. Moreover, this was not due to an indirect effect caused by checkpoint activation by DNA damage or replication defects. These observations suggest that CDK-1 activation in the C. elegans one-cell embryo is sensitive to the metabolic state of the cell, and that down-regulation of the TCA cycle prevents the removal of CDK-1 inhibitory phosphorylation. The TCA cycle was previously shown to be necessary for the development of the early embryo in mammals, but the molecular processes affected were not known. Our study demonstrates a link between the TCA cycle and a specific cell cycle transition in the one-cell stage embryo.
authors.affiliation: Laboratory of Cell and Molecular Biology, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892.
authors.forename: Mohammad M
authors.initials: MM
authors.lastname: Rahman
authors.forename: Simona
authors.initials: S
authors.lastname: Rosu
authors.forename: Daphna
authors.initials: D
authors.lastname: Joseph-Strauss
authors.forename: Orna
authors.initials: O
authors.lastname: Cohen-Fix
mesh_terms: D000818:Animals; D016203:CDC2 Protein Kinase / Q000378:metabolism; D017173:Caenorhabditis elegans / Q000196:embryology*; D002455:Cell Division / Q000502:physiology; D002952:Citric Acid Cycle / Q000235:genetics*; D015536:Down-Regulation / Q000502:physiology*; D005455:Fluorescent Antibody Technique; D018613:Microscopy, Confocal; D008938:Mitosis / Q000235:genetics / Q000502:physiology*; D010766:Phosphorylation; D034622:RNA Interference; D059008:Time-Lapse Imaging
chemical_list: D016203:CDC2 Protein Kinase