Regulation of Cell Division in Bacteria by Monitoring Genome Integrity and DNA Replication Status

Abstract

All organisms regulate cell cycle progression by coordinating cell division with DNA replication status. In eukaryotes, DNA damage or problems with replication fork progression induce the DNA damage response (DDR), causing cyclin-dependent kinases to remain active, preventing further cell cycle progression until replication and repair are complete. In bacteria, cell division is coordinated with chromosome segregation, preventing cell division ring formation over the nucleoid in a process termed nucleoid occlusion. In addition to nucleoid occlusion, bacteria induce the SOS response after replication forks encounter DNA damage or impediments that slow or block their progression. During SOS induction, Escherichia coli expresses a cytoplasmic protein, SulA, that inhibits cell division by directly binding FtsZ. After the SOS response is turned off, SulA is degraded by Lon protease, allowing for cell division to resume. Recently, it has become clear that SulA is restricted to bacteria closely related to E. coli and that most bacteria enforce the DNA damage checkpoint by expressing a small integral membrane protein. Resumption of cell division is then mediated by membrane-bound proteases that cleave the cell division inhibitor. Further, many bacterial cells have mechanisms to inhibit cell division that are regulated independently from the canonical LexA-mediated SOS response. In this review, we discuss several pathways used by bacteria to prevent cell division from occurring when genome instability is detected or before the chromosome has been fully replicated and segregated.

Keywords: DNA damage; SOS response; cell cycle; cell division; checkpoint.

FIG 1

A model for activation of the bacterial SOS response. Activation of the SOS response begins with accumulation of ssDNA that occurs when high levels of DNA damage are present (green polygons). The ssDNA is subsequently coated with the protein RecA. The resulting RecA/ssDNA nucleoprotein filament stimulates the protease activity of the transcriptional repressor LexA (yellow protein). LexA undergoes autocleavage, resulting in derepression of the LexA regulon. Many of the genes in the LexA regulon are involved in DNA repair, DNA damage tolerance, and regulation of cell division, a process known as a DNA damage checkpoint. Yellow boxes represent LexA binding sites, and purple boxes represent −35 and −10 promoter sequences. This figure is adapted from reference .

FIG 2

DNA damage-dependent cell cycle checkpoint in E coli. When E. coli cells encounter DNA damage (green polygons), the SOS response is activated, and the cell division inhibitor SulA is overexpressed (dark green). SulA prevents cell division by inhibiting assembly of the FtsZ ring (red circles). Following DNA repair and SOS termination, SulA is degraded by Lon protease, allowing cell division to proceed. This figure is adapted from reference .

FIG 3

DNA damage-dependent cell cycle checkpoint in B. subtilis. When B. subtilis cells encounter DNA damage (green polygons), the SOS response is activated, and the cell division inhibitor YneA is expressed. YneA prevents cell division through an unknown mechanism. CtpA (maroon) and DdcP (blue) cleave YneA, deactivating the DNA damage checkpoint. This figure is adapted from reference .

FIG 4

Model for SidA and DidA inhibition of cell division in Caulobacter spp. following DNA damage. SidA is regulated by LexA, and DidA is regulated by the transcription factor DriD. Following DNA damage, SidA (red) and DidA (purple) are expressed and interact with FtsW and FtsN, respectively (116). These interactions are hypothesized to cause the FtsW/I/N complex to assume an inactive state (116). The inhibition of FtsW/I/N prevents cytokinesis. This figure was adapted from PLoS Biology (116). The orientation of integral membrane proteins as well as membrane-spanning regions were predicted using Protter (122). C, C terminus; N, N terminus.