Mysterious Long-Range Four-Stranded DNA Structures Found To Play a Role in Rare Aging Disease

A special form of four-stranded DNADNA, or deoxyribonucleic acid, is a molecule composed of two long strands of nucleotides that coil around each other to form a double helix. It is the hereditary material in humans and almost all other organisms that carries genetic instructions for development, functioning, growth, and reproduction. Nearly every cell in a person’s body has the same DNA. Most DNA is located in the cell nucleus (where it is called nuclear DNA), but a small amount of DNA can also be found in the mitochondria (where it is called mitochondrial DNA or mtDNA).”>DNA, recently seen in human cells, has been found to interact with a gene that causes Cockayne Syndrome when faulty.

As well as the classic double-helix, researchers have recently discovered a whole host of other DNA strand configurations, including quadruple-helix DNA, which forms knot-like structures called G-quadruplexes.

While many of these new DNA configurations have only been observed in cells in dishes, G-quadruplexes have recently been observed in living human cells. However, their possible functions in cells have not been discovered.

Now, researchers from the Molecular Science Research Hub at Imperial College LondonEstablished on July 8, 1907, by Royal Charter, Imperial College London is a public research university in London with a focus on science, engineering, medicine, and business. Its main campus is located in South Kensington, and it has an innovation campus in White City, a research field station at Silwood Park, and teaching hospitals throughout London.”>Imperial College London have observed a protein called Cockayne Syndrome B (CSB) preferentially interacting with one specific type of G-quadruplex. These special G-quadruplexes arise when distant parts of DNA interact, something that researchers thought was impossible to form within cells.

Normally functioning CSB proteins do not cause any ill effects, but mutations of the gene that produce CSB protein can cause the fatal premature aging disorder Cockayne Syndrome, which kills many sufferers before adulthood.

The team found that CSB proteins with mutations that cause Cockayne Syndrome are no longer able to interact with the long-range G-quadruplexes. While we don’t yet know why this might be, the team’s results, published on December 2, 2021, in the Journal of the American Chemical Society, suggest that these long-range DNA G-quadruplexes are specifically linked with the functional role of CSB.

More complex interactions

Lead researcher Dr. Marco Di Antonio, from the Department of Chemistry at Imperial, said: “Our genomic DNA is more than two metres long, but is compressed into a space only a few microns in diameter. It shouldn’t therefore be a surprise that there are ways the long-range looped structures are leveraged to compress DNA in more complex interactions than we imagined.

“There is still so much we don’t know about DNA, but our results show that how and where G-quadruplex structures form affects their function, making them more important biologically than previously thought.”

DNA strands are incredibly long and are wound in tight structures to fit inside our cells. Previously, researchers had assumed that G-quadruplexes form only from regions of DNA that sit next to each other. However, the team discovered G-quadruplexes that are formed from parts of the DNA strand that are spatially distant one from the other.

It’s these G-quadruplexes that specifically interact with the CSB protein. The team shows that CSB could potentially use the G-quadruplexes to link together distant portions of the DNA.

Exactly what the interaction results in is yet to be determined, but previous independent research found that cells without CSB have difficulty processing the DNA around sequences with the potential to form G-quadruplexes.

The Imperial team has now found that the mutated form of CSB that causes Cockayne Syndrome is specifically attracted to G-quadruplexes that link distant DNA portions. This could mean further study of the mutated CSB gene might reveal the specific biological function of these long-range DNA structures.

Disease discoveries

Next, the researchers want to image the G-quadruplexes and the functional CSB gene bound together to determine exactly what the relationship does: whether the CSB helps the G-quadruplex hold the two distant regions of the DNA together, or whether CSB actually initiates the break-up of G-quadruplexes once they have completed their function, or a combination of both.

First author of the study Denise Liano, from the Department of Chemistry at Imperial, said: “There is currently no cure for Cockayne Syndrome.

“But with further study into how G-quadruplexes and the gene behind Cockayne Syndrome interact we can learn details that will hopefully allow us to discover therapeutic tools, such as designer molecules that can regulate the interaction and fight back against the premature aging caused by the disease.”

Reference: “Cockayne Syndrome B Protein Selectively Resolves and Interact with Intermolecular DNA G-Quadruplex Structures” by Denise Liano, Souroprobho Chowdhury and Marco Di Antonio, 2 December 2021, Journal of the American Chemical Society.
DOI: 10.1021/jacs.1c10745