Illustration of G-Quadruplexes. Credit: Federica Raguseo
An unique form of four-stranded DNA, just recently seen in human cells, has actually been discovered to interact with a gene that triggers Cockayne Syndrome when faulty.
In addition to the timeless double-helix, scientists have recently discovered a whole host of other DNA strand configurations, including quadruple-helix DNA, which forms knot-like structures called G-quadruplexes.
While much of these brand-new DNA setups have only been observed in cells in dishes, G-quadruplexes have actually just recently been observed in living human cells. Their possible functions in cells have actually not been found.
Now, researchers from the Molecular Science Research Hub at Imperial College London have observed a protein called Cockayne Syndrome B (CSB) preferentially engaging with one particular kind of G-quadruplex. These special G-quadruplexes occur when far-off parts of DNA interact, something that researchers believed was difficult to form within cells.
Usually functioning CSB proteins do not cause any ill effects, but mutations of the gene that produce CSB protein can trigger the deadly premature aging disorder Cockayne Syndrome, which kills many victims before their adult years.
The group found that CSB proteins with anomalies that trigger Cockayne Syndrome are no longer able to connect with the long-range G-quadruplexes. While we dont yet understand why this might be, the groups results, released on December 2, 2021, in the Journal of the American Chemical Society, recommend that these long-range DNA G-quadruplexes are specifically related to the practical function of CSB.
More intricate interactions
Lead scientist Dr. Marco Di Antonio, from the Department of Chemistry at Imperial, said: “Our genomic DNA is more than 2 metres long, but is compressed into a space just a couple of microns in diameter. It shouldnt therefore be a surprise that there are ways the long-range looped structures are leveraged to compress DNA in more intricate interactions than we envisioned.
” There is still a lot we dont learn about DNA, but our outcomes reveal that how and where G-quadruplex structures form affects their function, making them more crucial biologically than previously thought.”
DNA strands are extremely long and are wound in tight structures to fit inside our cells. Formerly, researchers had actually presumed that G-quadruplexes kind just from regions of DNA that sit beside each other. Nevertheless, the group found G-quadruplexes that are formed from parts of the DNA hair that are spatially far-off one from the other.
Its these G-quadruplexes that particularly engage with the CSB protein. The team reveals that CSB might potentially utilize the G-quadruplexes to connect together far-off portions of the DNA.
Precisely what the interaction results in is yet to be figured out, however previous independent research study found that cells without CSB have difficulty processing the DNA around sequences with the prospective to form G-quadruplexes.
The Imperial team has actually now found that the mutated type of CSB that triggers Cockayne Syndrome is particularly attracted to G-quadruplexes that connect distant DNA portions. This might imply additional study of the altered CSB gene might reveal the specific biological function of these long-range DNA structures.
Illness discoveries
Next, the researchers wish to image the G-quadruplexes and the practical CSB gene bound together to identify exactly what the relationship does: whether the CSB helps the G-quadruplex hold the 2 far-off areas of the DNA together, or whether CSB actually initiates the separation 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, stated: “There is currently no remedy for Cockayne Syndrome.
” But with more study into how G-quadruplexes and the gene behind Cockayne Syndrome connect we can learn information that will ideally enable us to discover therapeutic tools, such as designer particles that can manage the interaction and battle back versus the early aging brought on by the illness.”
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.1 c10745.