Mobile Menu

The role of G4s in Cockayne Syndrome

For the first time, researchers have demonstrated that the CSB protein, responsible for the premature ageing disorder Cockayne Syndrome, preferentially interacts with G4s formed from multiple DNA strands.

Cockayne Syndrome is a rare, fatal, premature ageing disorder. The condition is thought to occur in less than 3 newborns per 1 million in the US and Europe. It is characterised by an abnormally small head size, a failure to gain weight or grow at the expected weight intervals leading to very short stature, and delayed development.

Cockayne Syndrome results from mutations of the CSB gene, also known as the ERCC6 gene, which provides instructions for making proteins involved in damaged DNA repair. However, it is unclear how CSB mutations cause all of the varied features of this condition.

G4s in Cockayne Syndrome

Guanine-rich DNA can fold into secondary, knot-like structures called G-quadruplexes (G4s), which can either form from a single DNA strand or from multiple DNA strands. Historically, studies on the biological function of G4s formed by multiple DNA strands have been limited due to the low probability of them arising within genomic DNA.

But for the first time, researchers at Imperial College London observed that the CSB protein preferentially interacts with G4s formed from multiple DNA strands, with little to no binding towards G4s formed from a single DNA strand. Previously, it had been assumed that G4s only form from regions of DNA that sit next to each other, but this study demonstrated that G4s can in fact be formed from parts of the DNA strand that are spatially distant from one another. The results, published in the Journal of the American Chemical Society, indicate that G4s formed from multiple DNA strands are specifically associated with the functional role of CSB proteins.  

Exploring the relationship between G4s and CSB

Dr Marco Di Antonio, lead researcher in the study, 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 G4 structures form affects their function, making them more important biologically than previously thought.”

The fact that the mutated CSB gene is specifically attracted to G4s formed from distant DNA portions could mean that further study may reveal the specific biological mechanisms underlying Cockayne Syndrome. In the future, imaging the CSB gene bound to G4s may reveal the exact purpose of the relationship; whether the CSB helps the G4 hold distinct regions of DNA together, or whether CSB initiates the break-up of G4s once they have completed their function.

Denise Liano, first author of the study, explained:

“There is currently no cure for Cockayne Syndrome. But with further study into how G4s 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 ageing caused by the disease.”

Image credit: University of Cambridge

More on these topics

DNA / Mutations / Rare Diseases