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Supercoiling biases the formation of loops involved in gene regulation

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Abstract

The function of DNA as a repository of genetic information is well-known. The post-genomic effort is to understand how this information-containing filament is chaperoned to manage its compaction and topological states. Indeed, the activities of enzymes that transcribe, replicate, or repair DNA are regulated to a large degree by access. Proteins that act at a distance along the filament by binding at one site and contacting another site, perhaps as part of a bigger complex, create loops that constitute topological domains and influence regulation. DNA loops and plectonemes are not necessarily spontaneous, especially large loops under tension for which high energy is required to bring their ends together, or small loops that require accessory proteins to facilitate DNA bending. However, the torsion in stiff filaments such as DNA dramatically modulates the topology, driving it from extended and genetically accessible to more looped and compact, genetically secured forms. Furthermore, there are accessory factors that bias the response of the DNA filament to supercoiling. For example, small molecules like polyamines, which neutralize the negative charge repulsions along the phosphate backbone, enhance flexibility and promote writhe over twist in response to torsion. Such increased flexibility likely pushes the topological equilibrium from twist toward writhe at tensions thought to exist in vivo. A predictable corollary is that stiffening DNA antagonizes looping and bending. Certain sequences are known to be more or less flexible or to exhibit curvature, and this may affect interactions with binding proteins. In vivo all of these factors operate simultaneously on DNA that is generally negatively supercoiled to some degree. Therefore, in order to better understand gene regulation that involves protein-mediated DNA loops, it is critical to understand the thermodynamics and kinetics of looping in DNA that is under tension, negatively supercoiled, and perhaps exposed to molecules that alter elasticity. Recent experiments quantitatively reveal how much negatively supercoiling DNA lowers the free energy of looping, possibly biasing the operation of genetic switches.

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Acknowledgments

We are indebted to members of our laboratories and our collaborators who have contributed to our efforts to understand the contribution of supercoiling to loop-mediated gene regulation. For illustrations included here, we are grateful to Carlo Manzo, Hope Dennis, Zahra Pirani, Monica Fernandez-Sierra, Yue Ding, and Yan Yan. The work reviewed here was supported by the National Institutes of Health (GM084070 to LF and DD) and by the Emory University Research Council to DD.

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Correspondence to David Dunlap.

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Laura Finzi declares that she has no conflicts of interest.

David Dunlap declares that he has no conflicts of interest.

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This article is part of a Special Issue on ‘DNA supercoiling, protein interactions and genetic function’ edited by Laura Finzi and Wilma Olson.

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Finzi, L., Dunlap, D. Supercoiling biases the formation of loops involved in gene regulation. Biophys Rev 8 (Suppl 1), 65–74 (2016). https://doi.org/10.1007/s12551-016-0211-0

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