title: Nutritional Control of DNA Replication Initiation through the Proteolysis and Regulated Translation of DnaA.
abstract: Bacteria can arrest their own growth and proliferation upon nutrient depletion and under various stressful conditions to ensure their survival. However, the molecular mechanisms responsible for suppressing growth and arresting the cell cycle under such conditions remain incompletely understood. Here, we identify post-transcriptional mechanisms that help enforce a cell-cycle arrest in Caulobacter crescentus following nutrient limitation and during entry into stationary phase by limiting the accumulation of DnaA, the conserved replication initiator protein. DnaA is rapidly degraded by the Lon protease following nutrient limitation. However, the rate of DnaA degradation is not significantly altered by changes in nutrient availability. Instead, we demonstrate that decreased nutrient availability downregulates dnaA translation by a mechanism involving the 5' untranslated leader region of the dnaA transcript; Lon-dependent proteolysis of DnaA then outpaces synthesis, leading to the elimination of DnaA and the arrest of DNA replication. Our results demonstrate how regulated translation and constitutive degradation provide cells a means of precisely and rapidly modulating the concentration of key regulatory proteins in response to environmental inputs.
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany; Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.
authors.forename: David J
authors.initials: DJ
authors.lastname: Leslie
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany; Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Heinen
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany.
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Schramm
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany.
authors.forename: Marietta
authors.initials: M
authors.lastname: Thüring
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Aakre
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany; Max Planck Institute for Terrestrial Microbiology, Marburg, Germany.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Murray
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America; Howard Hughes Medical Institute, Massachusetts Institute of Technology, Cambridge, Massachusetts, United States of America.
authors.forename: Michael T
authors.initials: MT
authors.lastname: Laub
authors.affiliation: LOEWE Center for Synthetic Microbiology, Philipps University Marburg, Marburg, Germany; Department of Biology, Philipps University Marburg, Marburg, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jonas
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016935:Caulobacter crescentus / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000235:genetics; D002876:Chromosomes, Bacterial / Q000235:genetics; D004261:DNA Replication / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000235:genetics*; D015964:Gene Expression Regulation, Bacterial / Q000235:genetics; D049070:Protease La / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics; D059748:Proteolysis; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D013217:Starvation / Q000235:genetics
chemical_list: D020121:5' Untranslated Regions; D001426:Bacterial Proteins; D004268:DNA-Binding Proteins; C066312:DnaA protein, Bacteria; D049070:Protease La