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.
Highlights
The ability of cells to arrest their growth and proliferation in response to nutrient depletion or stressful conditions is typically critical for their survival
Several mechanisms have been reported in different bacteria that modulate DnaA activity to ensure the correct timing of DNA replication initiation [2]
We show that DnaA translation decreases as nutrients become scarce; this decrease in synthesis, combined with constitutive degradation by Lon rapidly eliminates DnaA and prevents DNA replication initiation
Summary
The ability of cells to arrest their growth and proliferation in response to nutrient depletion or stressful conditions is typically critical for their survival. Several mechanisms have been reported in different bacteria that modulate DnaA activity to ensure the correct timing of DNA replication initiation [2]. First elucidated in Escherichia coli and generally referred to as RIDA (regulatory inactivation of DnaA), involves ATP binding and hydrolysis [3,4]. ATP hydrolysis by DnaA can be stimulated (in E. coli) by the protein Hda bound to the DNA-loaded replicase clamp [6]. ATP hydrolysis inactivates DnaA and thereby helps prevent the re-initiation of DNA replication [4,7]. RIDA likely operates in other proteobacteria; DnaA activity or its access to the origin can be regulated in some bacteria by interacting proteins or sequestration mechanisms [2]
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