Feedback control of a master bacterial cell-cycle regulator

The transcriptional regulator CtrA controls several key cell-cycle events i n Caulobacter crescentus, including the initiation of DNA replication, DNA methylation, cell division, and flagellar biogenesis. CtrA is a member of t he response regulator family of two component signal transduction systems. Cartlobacter goes to great lengths to control the time and place of the act ivity of this critical regulatory factor during the cell cycle. These contr ols include temporally regulated transcription and phosphorylation and spat ially restricted proteolysis, We report here that ctrA expression is under the control of two promoters: a promoter (P1) that is active only in the ea rly predivisional cell and a stronger promoter (P2) that is active in the l ate predivisional cell. Both promoters exhibit CtrA-mediated feedback regul ation: the early P1 promoter is negatively controlled by CtrA, and the late P2 promoter is under positive feedback control. The CtrA protein footprint s conserved binding sites within the P1 and P2 promoters. We propose that t he P1 promoter is activated after the initiation of DNA replication in the early predivisional cell. The ensuing accumulation of CtrA results in the a ctivation of the P2 promoter and the repression of the P1 promoter late in the cell cycle. Thus, two transcriptional feedback loops coupled to cell cy cle-regulated proteolysis and phosphorylation of the CtrA protein result in the pattern of CtrA activity required for the temporal and spatial control of multiple cell-cycle events.