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Sizing up the bacterial cell cycle

Key Points

  • Simple models combined with quantitative time-lapse measurements of cell growth and division are an essential first step towards generating and falsifying mechanistic hypotheses for the homeostasis of cell size and the cell cycle.

  • The recently discovered adder paradigm for cell size control, in which cells add a fixed amount of material between consecutive divisions or DNA replication initiations, has been established in several bacterial species and seems to be widespread. However, the vast majority of bacterial phyla have not yet been investigated.

  • Classic and recent data have indicated that average cell size depends on three key variables: the concentration of DNA replication initiation sites, the average time between DNA replication initiation and cell division, and the mass-doubling time. This dependence accounts for the classic Growth Law, which links cell size to the nutrient quality of the medium, and highlights the need for the simultaneous measurement of a range of cell variables to investigate cell size mutants or perturbations.

  • DnaA, MreB and FtsZ are key regulators of DNA replication initiation, cell growth and cell division, respectively, but currently there is no overarching view of how molecular mechanisms coordinate cell cycle events and cell growth to achieve cell size control and robust genome inheritance.

Abstract

It is remarkable how robustly a bacterial species can maintain its preferred size. This capacity is intimately related to control of the cell cycle: cell size and growth rate determine the duration of the cell cycle, which must accommodate the initiation and completion of DNA replication, and the assembly of the division apparatus during steady growth. Although we still lack an integrated view of the interconnections among events in the cell cycle, cell growth and cell size, the development of high-throughput imaging and image-processing protocols has stimulated a renaissance in the field. In this Review, we summarize recent findings, present simple classic models for cell size control, introduce high-throughput data-collection techniques, and explore the mechanisms that coordinate cell size with essential growth and cell cycle processes.

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Figure 1: Quantifying the control of cell size.
Figure 2: The Helmstetter–Cooper model of the bacterial cell cycle.
Figure 3: Cell size regulation and the Growth Law.
Figure 4: Spatial localization of molecular determinants of cell size.

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Acknowledgements

The authors thank the Huang laboratory, L. Harris and P. Levin for helpful discussions. Work was supported, in part, by NSF CAREER Award MCB-1149328 (to K.C.H.) and the Allen Discovery Center at Stanford University on Systems Modeling of Infection (to K.C.H.). The authors regret that, owing to the broad scope of this Review and space constraints, many excellent and arguably relevant studies could not be cited.

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L.W. and K.C.H. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and edited the manuscript before submission.

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Correspondence to Lisa Willis or Kerwyn Casey Huang.

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The authors declare no competing financial interests.

PowerPoint slides

Glossary

oriC

The origin of replication; a highly conserved DNA sequence on the bacterial chromosome from which bidirectional DNA replication is initiated.

Growth Law

For the model bacteria Escherichia coli and Salmonella enterica subsp. enterica serovar Typhimurium, average cell size increases as the nutritional quality of the growth medium improves and hence as cells grow faster. This size increase depends on growth rate alone and not on the chemical composition of the medium.

DnaA

A highly conserved protein that triggers the initiation of DNA replication following binding to ATP and multiple specific DnaA-binding sequences within oriC. DnaA is a strong candidate for participating in cell size control.

FtsZ

A bacterial homologue of eukaryotic tubulin and the key regulator of cell division.

MreB

A bacterial homologue of eukaryotic actin that functions as the spatial scaffold for the patterning of insertion of new cell wall material in many rod-shaped species.

Exponential growth

Cells that grow exponentially have an absolute growth rate that is proportional to cell size throughout the cell cycle. Other growth kinetics are possible, such as linear kinetics, in which the absolute growth rate is constant throughout the cell cycle, regardless of cell size.

Min proteins

The Escherichia coli Min system (proteins MinC, MinD and MinE) participates in locating the septum at mid-cell through spatiotemporal oscillations of membrane-bound Min proteins that inhibit FtsZ assembly at the cell poles.

Replisomes

Molecular complexes that are located at a replication fork that carry out DNA replication.

Origin firing

The beginning of a new round of DNA replication when, facilitated by DnaA, the oriCs unwind for replisome loading.

Mother machine

A microfluidic device in which nutrients are continually replenished and cells are trapped in narrow channels, continually growing and dividing at a steady density. This device enables cell tracking over many generations in a stable environment.

Z-ring

A band of polymerized FtsZ at mid-cell, the assembly of which is the first known step in cell division.

Membrane elution technique

Method for eluting newborn cells from a growing culture (also known as the baby machine) in which cells are initially bound to a membrane. As the culture grows, only newborn non-membrane- bound sister cells are eluted. The temporal order of cell elution is inversely related to cell age, yielding correlations between cell age and other cellular variables, such as DNA synthesis rate, that are pulse-labelled before elution.

SOS response

An inducible DNA damage repair system that is widely present among bacteria and that is comprised of two key proteins in Escherichia coli: a default repressor and a DNA damage-induced de-repressor.

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Willis, L., Huang, K. Sizing up the bacterial cell cycle. Nat Rev Microbiol 15, 606–620 (2017). https://doi.org/10.1038/nrmicro.2017.79

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