Metabolism, cell growth and the bacterial cell cycle

Abstract

Adaptation to fluctuations in nutrient availability is a fact of life for single-celled organisms in the 'wild'. A decade ago our understanding of how bacteria adjust cell cycle parameters to accommodate changes in nutrient availability stemmed almost entirely from elegant physiological studies completed in the 1960s. In this Opinion article we summarize recent groundbreaking work in this area and discuss potential mechanisms by which nutrient availability and metabolic status are coordinated with cell growth, chromosome replication and cell division.

Figure 1. The bacterial cell cycle

The bacterial cell cycle is traditionally divided into three stages: the period between division (birth) and the initiation of chromosome replication (the B period); the period required for chromosome replication (the C period); and the time between the completion of chromosome replication and the completion of cell division (the D period). The bacterial cells (in this case, Escherichia coli) are outlined in black and contain highly schematic chromosomes (purple ovals) with oriC regions shown as green circles.

Figure 2. Nutrient availability, DNA replication and chromosome segregation

Green boxes represent the relevant events in the cell cycle. a| Nutrient availability is a key determinant for replication initiation. The production of the initiation protein DnaA and other essential components of the replication machinery is proportional to carbon availability and growth rate. Amino acid starvation directly inhibits replication initiation through the production of guanosine tetraphosphate and guanosine pentaphosphate (collectively known as (p)ppGpp). Growth rate might also affect initiation indirectly, potentially through the additional feedback mechanisms that transmit the cell cycle and replication status to the replication machinery, to prevent overinitiation. For example, DnaA represses the transcription of the dnaA operon. In addition, DnaA binding to loci other than the origin of replication (oriC), such as datA in Escherichia coli, titrates DnaA and thereby inhibits replication initiation; replication doubles the copy number of datA, further titrating DnaA. In E. coli, newly replicated oriC contains hemimethylated GATC sites, which are sequestered to prevent reinitiation. Finally, replication elongation inhibits re-initiation through Hda in E. coli or YabA in Bacillus subtilis. The beta clamp, encoded by dnaN, is essential for mediating this control. b| Nutrient availability and amino acid starvation also affect replication elongation and chromosome segregation.

Figure 3. Spatial and temporal regulation of cell division is achieved through multiple layers of control

a| FtsZ assembly is coordinated with the initiation of DNA replication and nucleoid segregation to ensure that daughter cells receive complete copies of the bacterial genome. b| In Bacillus subtilis, the glucolipid biosynthesis pathway serves as a metabolic sensor to transmit information about carbon availability and growth rate, through the intracellular UDP–glucose concentration, to the division apparatus. When this sensor is functional (top), division is coupled to the achievement of a specific size (termed ‘critical mass’) as well as to mass doubling time. When this sensor is defective (bottom), division is uncoupled from the achievement of critical mass but remains sensitive to mass doubling time, resulting in reduced cell size.