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Allostery through DNA drives phenotype switching.

Gabriel Rosenblum1, Nadav Elad2, Haim Rozenberg3

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DNA transmits allosteric signals to enhance transcription factor binding cooperativity. This mechanism regulates gene expression by altering DNA curvature, offering insights into genetic circuit dynamics.

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Area of Science:

  • Molecular Biology
  • Biophysics
  • Genetics

Background:

  • Allostery is a fundamental protein regulation mechanism.
  • Emerging evidence suggests DNA can also transmit allosteric signals.
  • The role of DNA-mediated allostery in gene expression regulation was previously unclear.

Purpose of the Study:

  • To investigate if DNA transmits allosteric signals over long distances.
  • To determine the mechanism by which DNA-mediated allostery affects transcription factor binding.
  • To explore the implications for gene expression regulation and genetic circuit design.

Main Methods:

  • Single-molecule Förster Resonance Energy Transfer (smFRET) to observe protein-DNA interactions.
  • Cryo-electron microscopy (Cryo-EM) to determine high-resolution structures.
  • Genetic manipulation of DNA spacer sequences to study allosteric effects.

Main Results:

  • Demonstrated that DNA transmits allosteric signals between distant transcription factor binding sites.
  • Showed that ComK binding at one site enhances affinity at a remote site in Bacillus subtilis.
  • Identified altered DNA curvature, driven by mechanical forces, as the mechanism for signal transmission.
  • Confirmed that modifying DNA spacer length tunes cooperativity.

Conclusions:

  • DNA actively transmits allosteric signals to regulate transcription factor binding cooperativity.
  • DNA-mediated allostery, through mechanical force and DNA curvature changes, is a key mechanism in gene expression.
  • This mechanism allows for fine-tuning of genetic circuit dynamics and provides a basis for controlling gene expression.