Protein binding to “hidden” DNA- An intriguing concept!

Sneha Singhal, Jaypee Institute of information technology, Noida

DNA is present in the form of chromatin fibers tightly wrapped around histones in the cell nucleus. Therefore, rendering the large fraction of DNA surface inaccessible for protein binding. For this problem, several studies began to uncover the various strategies used by DNA-binding proteins. Scientists proposed that how a specific stretch of DNA is recognized by a protein when DNA is hidden.

On contributing to a better understanding of how proteins bind a specific stretch of DNA, scientists determined for the first time the structure of a protein bound to DNA about 35 years ago. DNA binding proteins of eukaryotes operate in the context of chromatin, DNA in the cell is wrapped around histone proteins that form nucleosomes (the elementary building blocks of chromatin). Most of the studies since then have been conducted in a test tube on isolated DNA. It becomes inaccessible to other proteins such as transcription factors (TFs) or repair enzymes to bind with a DNA sequence close to histones. So different strategies are needed for DNA-binding proteins to interact when DNA is package in a chromatin fiber.

Thomä’s group studied the interaction of proteins with DNA in the context of chromatin from a structural perspective. The Thomä, Schübeler groups at the FMI, and many laboratories, solved several structures of DNA binding proteins on the nucleosome. Cryo-electron microscopy (cryo-EM) technology allows visualization of complex assemblies at the molecular level and structural insights of DNA binding proteins were made possible only by this technique. Alicia Michael, a postdoc in the Thomä lab, and Nicolas Thomä intrigued by these structural insights, discuss the interplay in a review article between the DNA-binding proteins with specific DNA sequences (also called hidden DNA) or modifications on nucleosomes.

Michael said from all these studies that a key conclusion is that the position of the DNA binding site and that of nucleosome matter. Scientists believed that nucleosomes were just amorphous obstacles for DNA binding proteins, but now we can tell that it’s a lot more complex as we can precisely look at the molecular details cause by cryo-EM technology. Michael explained, when a protein sequence bind with DNA, it depends on several factors. The position of the DNA binding fold (the part of the protein that binds to DNA) and the DNA binding site on the nucleosome matter. Nevertheless, chromatin obstructed the first responders in DNA repair and sequence-specific transcription factors that bind to DNA target sites. It is only now beginning to emerge how DNA sequences are interrogated on nucleosomes, while early studies examined protein binding to histone-free DNA. Nucleosomes can let a transcription factor or a repair protein bind by selectively giving access to a binding site. TFs (transcription factors) or repair enzymes are ideally suited to gate access for gene regulation and DNA repair.

Still, many questions were remaining for example, throughout the genome, remodelers can put nucleosomes in certain positions, so to what extent DNA binding proteins require assistance from other proteins. However, Thomä said that over the past few years progress made in the field has been phenomenal. There is no such rule as what we know about proteins binding isolated DNA and proteins binding DNA on nucleosomes. Fundamental principles of the structures and analysis were how regulation and repairing of the genome of eukaryotes—from yeast to humans has been understood.

Also read: Synthetic Biological Circuit for faster response

References:

1. Michael, A. K., & Thomä, N. H. (2021). Reading the chromatinized genome. Cell, S0092-8674(21)00659-0. Advance online publication. https://doi.org/10.1016/j.cell.2021.05.029

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