Four-stranded DNA structures play a role in the disease of aging

A special form of four-stranded DNA recently seen in human cells has been shown to interact with a gene that causes Cockayne syndrome when defective.

In addition to the classic double helix, researchers recently discovered a whole host of other DNA strand configurations, including quadruple helix DNA, which forms node-like structures called G-quadruplexes.

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

Now, researchers at Imperial College London’s Molecular Science Research Hub have observed a protein called Cockayne Syndrome B (CSB) that preferentially interacts with a specific type of G-quadruplex. These special G-quadruplexes appear when distant parts of DNA interact, which the researchers thought was impossible to form in cells.

Normal functioning CSB proteins do not cause any ill effects, but mutations in the gene that produces the CSB protein can cause Cockayne syndrome, a fatal disorder of premature aging, which kills many people before adulthood.

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

Principal Investigator Dr Marco Di Antonio, Imperial’s Department of Chemistry, said: “Our genomic DNA is over two meters long, but is compressed into a space only a few microns in diameter. So it shouldn’t be surprising that there are ways to harness long-range loop structures to compress DNA into more complex interactions than we ever imagined.

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

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

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

The exact results of the interaction are yet to be determined, but previous independent research has found that cells without CSB have difficulty processing DNA around sequences that may form G-quadruplexes.

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

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

The study’s first author, Denise Liano, of the Department of Chemistry at Imperial, said: “There is currently no cure for Cockayne syndrome. But with further study of how G-quadruplexes and the gene that causes Cockayne syndrome interact, we can learn details that will hopefully allow us to uncover therapeutic tools, such as molecules. that can regulate the interaction and combat premature aging caused by disease. . “

Reference: Liano D, Chowdhury S, Di Antonio M. Cockayne Syndrome Protein B selectively resolves and interacts with G-Quadruplex structures of intermolecular DNA. J Am Chem Soc. 2021. doi: 10.1021 / jacs.1c10745

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