Journal
CELL
Volume 154, Issue 3, Pages 623-636Publisher
CELL PRESS
DOI: 10.1016/j.cell.2013.06.034
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Funding
- National Institutes of Health grant [5R01GM082899, R00GM084157]
- German Research Foundation (DFG) [JO 925/1-1]
- University of Massachusetts as part of the Chemistry-Biology Interface Training Program [T32 GM08515]
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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.
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