Dynamic DNA Allostery: A Novel Type of Allostery for Transcription and Beyond
Allostery is a property of many biological macromolecules, in which the effect of binding of a ligand at one site is transmitted to another, distal site, allowing for regulation of the macromolecule’s function. For example, in hemoglobin, the oxygen carrier in our blood, the binding of an oxygen molecule induces conformational changes within hemoglobin promoting more oxygen binding. Many other proteins are known to have allosteric properties, but how about the DNA genome, a giant macromolecule residing at the core of every living cell? Does the genome possess allosteric properties? How? And what would be the functional consequences? These are the questions that my lab is trying to answer.
The genome contains long DNA strands (in the order of meters, if stretched out), folded like a jumble of spaghetti. So far, DNA is considered as a mere template providing base sequences for genes and binding sites for regulatory proteins, but growing evidence suggests that DNA can transmit mechanical perturbations applied at a site to distal regions, affecting various molecular events happening on the DNA.
We are trying to understand the mechanism of DNA allostery by characterizing the physical properties of DNA that allow for the dynamic transmission of information along the DNA strands. We are combing tools from single-molecule biophysics to apply mechanical perturbations on the DNA and visualize the transmission of small changes occurring on the same DNA in high spatial and temporal resolution. We will also study how allosteric properties of DNA affect transcription, the first step of gene expression where RNAs are produced from DNA, and gene mutations, another critical process happening on the DNA, often leading to evolution and diseases.
Our work will provide new insights into the genome’s physical properties and functions and would point toward new ideas and methods to control gene expression and gene evolution—which have potential therapeutic applications for treating a wide range of human diseases.