Cyclic di-GMP acts as a cell cycle oscillator to drive chromosome replication

Area of Science:

• Microbiology
• Molecular Biology
• Cell Biology

Background:

• Eukaryotes coordinate cell division and differentiation using cyclins and cyclin-dependent kinases.
• Bacterial regulatory systems for balancing cell division and fate decisions are poorly understood.
• Mechanisms tuning bacterial division with developmental programs require elucidation.

Purpose of the Study:

• To investigate the role of cyclic diguanylate (c-di-GMP) in coordinating the cell cycle of Caulobacter crescentus.
• To elucidate how c-di-GMP regulates the essential cell cycle kinase CckA.
• To understand the spatial control of CckA by c-di-GMP during bacterial cell division.

Main Methods:

• Measurement of oscillating cyclic diguanylate (c-di-GMP) levels.
• Demonstration of direct binding of c-di-GMP to the CckA kinase.
• Analysis of c-di-GMP's effect on CckA kinase and phosphatase activity.
• Investigation of c-di-GMP's spatial control over CckA during cell division.

Main Results:

• Oscillating c-di-GMP levels drive the Caulobacter crescentus cell cycle.
• c-di-GMP directly binds to CckA, inhibiting kinase and stimulating phosphatase activity.
• An increase in c-di-GMP switches CckA to phosphatase mode, enabling replication and cell cycle progression.
• c-di-GMP spatially controls CckA to establish replication asymmetry in daughter cells.

Conclusions:

• c-di-GMP acts as a bacterial cyclin-like molecule, coordinating chromosome replication with cell morphogenesis.
• This c-di-GMP-mediated control mechanism is conserved in other bacteria, like Agrobacterium tumefaciens.
• c-di-GMP represents a general mechanism regulating bacterial behavior, persistence, and proliferation.