title: Proteotoxic stress induces a cell-cycle arrest by stimulating Lon to degrade the replication initiator DnaA.
abstract: The decision to initiate DNA replication is a critical step in the cell cycle of all organisms. Cells often delay replication in the face of stressful conditions, but the underlying mechanisms remain incompletely defined. Here, we demonstrate in Caulobacter crescentus that proteotoxic stress induces a cell-cycle arrest by triggering the degradation of DnaA, the conserved replication initiator. A depletion of available Hsp70 chaperone, DnaK, either through genetic manipulation or heat shock, induces synthesis of the Lon protease, which can directly degrade DnaA. Unexpectedly, we find that unfolded proteins, which accumulate following a loss of DnaK, also allosterically activate Lon to degrade DnaA, thereby ensuring a cell-cycle arrest. Our work reveals a mechanism for regulating DNA replication under adverse growth conditions. Additionally, our data indicate that unfolded proteins can actively and directly alter substrate recognition by cellular proteases.
authors.affiliation: Department of Biology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
authors.forename: Kristina
authors.initials: K
authors.lastname: Jonas
authors.forename: Jing
authors.initials: J
authors.lastname: Liu
authors.forename: Peter
authors.initials: P
authors.lastname: Chien
authors.forename: Michael T
authors.initials: MT
authors.lastname: Laub
mesh_terms: D001426:Bacterial Proteins / Q000235:genetics / Q000378:metabolism*; D016935:Caulobacter crescentus / Q000166:cytology* / Q000235:genetics / Q000502:physiology*; D004261:DNA Replication; D004269:DNA, Bacterial / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004926:Escherichia coli / Q000378:metabolism; D006360:Heat-Shock Proteins / Q000378:metabolism; D018869:Heat-Shock Response; D018832:Molecular Chaperones / Q000378:metabolism; D049070:Protease La / Q000378:metabolism*; D017510:Protein Folding; D012808:Sigma Factor / Q000378:metabolism; D013312:Stress, Physiological
chemical_list: D001426:Bacterial Proteins; D004269:DNA, Bacterial; D004268:DNA-Binding Proteins; C066312:DnaA protein, Bacteria; D006360:Heat-Shock Proteins; D018832:Molecular Chaperones; D012808:Sigma Factor; C069774:heat-shock sigma factor 32; D049070:Protease La
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