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Four-stranded DNA structure interactions play role in ageing syndrome

13 December 2021
Appeared in BioNews 1125

A protein that is known to be affected in people with the rare ageing disease Cockayne syndrome, has been shown to interact with four-stranded DNA.

While four-stranded DNA has been observed in human cells (see BioNews 1057), little was known about its role. Four-stranded DNA, also known as G-quadruplexes, are thought to have roles in transcription, and are accumulated in cancerous cells (see BioNews 1079). Now researchers from Imperial College London have observed how formation of four-stranded DNA affects its interactions with a specific protein and have published their findings in the Journal of the American Chemical Society.

Lead author of the study Dr Marco Di Antonio said: '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.'

Four-stranded DNA can be formed from one double-stranded DNA folding back in on itself (intramolecular) or from multiple DNA strands attaching to each other (intermolecular). Past research on four-stranded DNA largely focused on forms that had been formed from DNA folding back on itself. This latest study is the first to report that the Cockayne syndrome B (CSB) protein selectively binds to four-stranded DNA that formed from multiple DNA strands attaching to each other, in ribosomal DNA (rDNA), suggesting that four-stranded DNA may bind to different proteins and have different biological functions based on how it formed.

Cockayne syndrome is a genetic disorder characterised by premature ageing caused by a mutation in the CSB gene, which codes for the CSB protein.

In the study, researchers investigated how the CSB protein interacted with differently formed versions of four-stranded DNA, which shared the same sequence but were formed intramolecularly or intermolecularly within rDNA. They found the CSB protein bound to four-stranded DNA formed via intermolecular interactions with ~1000-fold higher selectivity. The team found that CSB proteins with mutations that cause Cockayne syndrome were not able to interact with the four-stranded DNA, which led to an accumulation of them within cells. 

Since loss of CSB function is known to affect people with Cockayne syndrome, the study findings suggest that the build-up of quadruplexes could be behind the accelerated ageing phenotype seen in these individuals. 

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