The double helix structure of DNA is embedded into the heart of popular science. Since its discovery in 1953, its structure has captured the hearts and minds of those who are a little bit curious as to how such a symmetrical structure came to control the flow of life from its roots to the present day.
Despite its position, however, DNA too is subject to unique and odd happenings that may otherwise affect its expression. This lies at the very heart of genetic disorders, which account for 2%-5% of all live births, according to a fact sheet from the World Health Organization.
One such inherited ailment is what’s known as Cockayne Syndrome (CS), which is a particular aging syndrome and classified as a rare form of dwarfism, according to the National Organization for Rare Disorders. CS is characterized by heightened sensitivity to light, premature aging, growth failure, and brain degeneration.
In line with this, researchers from the Imperial College London (ICL) are on the case to determine what exactly may lead to the development of CS—and it may be intertwined with a particular DNA misconfiguration. Their results were published in the Journal of the American Chemical Society.
ICL researchers recognize that a particular link has already been found between CS and a mutation in a particular protein known as the Cockayne Syndrome B (CSB) protein. Now, new findings from the ICL team found a particular affinity that CSB protein has for a particular type of substance known as a G-quadruplex—essentially “quadruple-stranded knots” of multiple DNA strands.
These G-quadruplexes are DNA strands that either double back on themselves or attach themselves to another double-strand of DNA. They were discovered back in 2013, and have since been found in considerably high concentrations inside cancerous cells.
Now, the new study from ICL researchers links their presence to the eventual appearance of CS due to the CSB protein exhibiting “astonishing […] affinity” towards G-quadruplexes “formed from multiple DNA strands,” according to LiveScience. To the team, this means that CSB proteins play a role in ribosomal DNA strand matching within the cell nucleus.
Essentially, these forms of DNA are responsible for the transcription of certain cellular proteins. Thus, if the CSB is somehow mutated and therefore dysfunctional, they can no longer bind to the G-quadruplexes—meaning the G-quadruplexes are left “unreadable.” At that point, cellular proteins are left unmade, and genetic information fails to leave the cell to communicate with the rest of the body.
As such, according to the authors, the onset of CS may be caused by the interruption in the production of proteins coded for by particular G-complexes within the body; this leads to the symptoms we now associate with CS, like premature aging and loss of certain sensory functions like sight.
“Given that CSB loss of function elicits premature aging phenotypes, our findings indicate that the interaction between CSB and ribosomal DNA intermolecular G4s is essential to maintain cellular homeostasis,” the authors elaborate in their paper.
Said primary author and ICL chemical biologist Mardo Di Antonio: “Our genomic DNA is more than two meters 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.”
Di Antonio continued: “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.”
In line with this, the authors hope that their findings help inform attempts to curb the effects of CS in the future, which may entail stopping dysfunctional CSB proteins from interacting with particular G-complexes within the body.
(For more genetics news, check out how they determined the mass of human chromosomes. Afterward, read further on how machine learning found a “ghost lineage” deep within the human genome.)
References
- Cassella, C. (2021, December 8). Unusual ‘quadruple helix’ structure in dna may be behind rare aging syndrome. ScienceAlert. https://www.sciencealert.com/an-unusual-four-stranded-structure-in-dna-could-be-behind-a-rare-aging-disease
- Cockayne syndrome. (n.d.). National Organization for Rare Disorders. Retrieved 16 December 2021, from https://rarediseases.org/rare-diseases/cockayne-syndrome/
- Hamamy, H. & Alwan, A. (1997). Genetic disorders and congenital abnormalities strategies for reducing the burden in the Region. EMHJ – Eastern Mediterranean Health Journal, 3 (1), 123-132, 1997. https://apps.who.int/iris/handle/10665/117084
- Liano, D., Chowdhury, S., & Di Antonio, M. (2021). Cockayne syndrome b protein selectively resolves and interact with intermolecular dna g-quadruplex structures. Journal of the American Chemical Society, 143(49), 20988–21002. https://doi.org/10.1021/jacs.1c10745
- Spiegel, J., Adhikari, S., & Balasubramanian, S. (2020). The structure and function of dna g-quadruplexes. Trends in Chemistry, 2(2), 123–136. https://doi.org/10.1016/j.trechm.2019.07.002
