4.5 Article

CcrZ is a pneumococcal spatiotemporal cell cycle regulator that interacts with FtsZ and controls DNA replication by modulating the activity of DnaA

Journal

NATURE MICROBIOLOGY
Volume 6, Issue 9, Pages 1175-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41564-021-00949-1

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Funding

  1. FRIMEDBIO grant from the Research Council of Norway [250976]
  2. JPIAMR grant from the Research Council of Norway [296906]
  3. Wellcome Trust Senior Research Fellowship [204985/Z/16/Z]
  4. Biotechnology and Biological Sciences Research Council [BB/P018432/1]
  5. National Institute of General Medical Sciences of the National Institutes of Health [R37 GM041934, R35 GM122538]
  6. Swiss National Science Foundation [31003A_172861, 51NF40_180541, 40AR40_185533]
  7. Novartis Foundation grant [17B064]
  8. ERC consolidator grant [771534-PneumoCaTChER]
  9. Wellcome Trust [204985/Z/16/Z] Funding Source: Wellcome Trust
  10. Swiss National Science Foundation (SNF) [40AR40_185533, 51NF40_180541, 31003A_172861] Funding Source: Swiss National Science Foundation (SNF)

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CcrZ is a conserved and essential protein in bacteria that coordinates DNA replication and cell division by controlling the activity of DnaA, ensuring proper chromosome inheritance by daughter cells. This mechanism highlights the importance of CcrZ in regulating the bacterial cell cycle.
Most bacteria replicate and segregate their DNA concomitantly while growing, before cell division takes place. How bacteria synchronize these different cell cycle events to ensure faithful chromosome inheritance by daughter cells is poorly understood. Here, we identify Cell Cycle Regulator protein interacting with FtsZ (CcrZ) as a conserved and essential protein in pneumococci and related Firmicutes such as Bacillus subtilis and Staphylococcus aureus. CcrZ couples cell division with DNA replication by controlling the activity of the master initiator of DNA replication, DnaA. The absence of CcrZ causes mis-timed and reduced initiation of DNA replication, which subsequently results in aberrant cell division. We show that CcrZ from Streptococcus pneumoniae interacts directly with the cytoskeleton protein FtsZ, which places CcrZ in the middle of the newborn cell where the DnaA-bound origin is positioned. This work uncovers a mechanism for control of the bacterial cell cycle in which CcrZ controls DnaA activity to ensure that the chromosome is replicated at the right time during the cell cycle. In this Article, the authors identify CcrZ as a protein that coordinates DNA replication and cell division in Streptococcus pneumoniae and other Firmicutes. CcrZ is localized to the division site by binding directly to the divisome protein FtsZ, and there it activates DnaA, the master initiator of DNA replication, through a still unknown mechanism.

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