Short stature, rapid ageing (progeria), severe photosensitivity, and moderate to severe learning delay are all symptoms of Cockayne syndrome (CS). A new study from Imperial College London’s Molecular Science Research Hub shows how a novel kind of four-stranded DNA, newly discovered in human cells, interacts with a gene that causes CS when it is defective.
Cockayne Syndrome B Protein
“Cockayne Syndrome B Protein Selectively Resolves and Interacts with Intermolecular DNA G-Quadruplex Structures,” a paper titled “Cockayne Syndrome B Protein Selectively Resolves and Interacts with Intermolecular DNA G-Quadruplex Structures,” was published in the Journal of the American Chemical Society.
The researchers discovered that a protein called Cockayne Syndrome B (CSB) interacts preferentially with one form of G-quadruplex. These unique G-quadruplexes occur when two pieces of DNA connect, something that scientists previously thought was impossible to achieve within cells.
Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s)
The researchers said, “Guanine-rich DNA can fold into secondary structures known as G-quadruplexes (G4s).” “G4s can be formed from a single DNA strand (intramolecular) or many DNA strands (intermolecular), although investigations on their biological roles have typically focused on intramolecular G4s due to the low likelihood of intermolecular G4s forming within genomic DNA.
“We present the first example of an endogenous protein, CSB, that can bind preferentially to intermolecular G4s produced within rDNA with picomolar affinity while showing insignificant binding to intramolecular structures.” We discovered that CSB prefers to resolve intermolecular G4s over intramolecular G4s, indicating that its preference for intermolecular structures is reflected at the resolvase level.”
CSB proteins with mutations that cause CS are no longer able to interact with long-range G-quadruplexes, according to the researchers.
“Our genomic DNA is more over two metres long, but it is compressed into a space barely a few millimetres in diameter,” said Imperial College chemistry professor Marco Di Antonio, PhD. “It shouldn’t come as a surprise, then, that long-range looped structures can be used to compress DNA in more complex interactions than we previously thought.”
“We still don’t know a lot about DNA, but our findings suggest that the way and where G-quadruplex structures arise has an impact on their function, making them more biologically significant than previously assumed.”
G-quadruplexes, which link distant DNA segments, are attracted to the mutant version of CSB that causes CS. Further research into the mutant CSB gene could reveal the biological purpose of these long-range DNA structures.
Mutations in either the ERCC8 (CSA) or ERCC6 (CSB) genes cause Cockayne syndrome. Autosomal recessive inheritance is the most common type of inheritance. Type 2 is the most severe, and those who are infected rarely live into childhood. Type 3 people live into their forties and fifties (Source: 01 )
The gene that causes CS-type I has been found on chromosome 5 and is known as ERCC8. ERCC6 is the gene for CS-type II, which has been localised to chromosome 10q11. About 75% of cases are caused by mutations in ERCC6, while 25% of cases are caused by mutations in ERCC8. (Source: 02 )
“At the moment, there is no therapy for Cockayne Syndrome,” said Denise Liano, a PhD student in Imperial College’s Department of Chemistry. “However, with more research into how G-quadruplexes and the gene that causes Cockayne Syndrome to interact, we can learn information that will hopefully lead to the discovery of therapeutic tools, such as designer molecules that can regulate the connection and combat the disease’s accelerated ageing.”