Stringent control of initiation of chromosomal replication in Bacillus subtilis

Interconnecting regulatory networks are characteristic of probably all cellular systems. Such ‘regulons’ allow the cell to respond in a coordinated manner to changes in its environment, including a rapid return to balanced growth after stress1,2. A regulon is usually composed of diverse metabolic pathways whose activities are amplified or inhibited by regulatory proteins, through the action of a small molecule, an alarmone3. Thus, for example, when the level of any aminoacyl transfer RNA becomes limiting in the bacterial cell, the stringent response is initiated; this is mediated through the nucleotide ppGpp and leads to the inhibition of synthesis of several major macromolecules, including stable RNA4,5. Surprisingly, the key control point in the cell cycle, initiation of DNA replication, has not previously been implicated in the stringent response. Using a Bacillus subtilis mutant in which the transcriptional step of initiation can be studied independently of any requirement for protein synthesis6, we now show that initiation of chromosomal replication is indeed subject to stringent control.