So, DNA. It’s a code; it’s made up of four letters, and it’s essential for life. Scientists worked out the sequence of the entire human genome about a decade ago (that’s all the DNA code in your body) so what else is there to know? A lot, says Barbara Xella – it turns out DNA can form all sorts of 3D structures, and if these odd formations aren’t recognized properly by proteins inside the cell, it can be deadly.
A little more than 50 years ago we didn’t know anything about DNA.
When many of the senior molecular biologists of our time were children, what would have become the subject of their studies and the main interest of their adult lives hadn’t even been discovered yet.
It’s a thought that has always fascinated me.
The information contained in DNA controls every single step during our development, from conception to death – so it’s pretty fundamentally important to understand how it works.
The problem is – the more we study DNA, the more levels of complexity we encounter.
Initially DNA looked simply like a linear molecule carrying genetic information to the next generation. Soon enough though, we were faced with the evidence that linearity only maybe resides in the sequence of the DNA code itself, and that there’s nothing really ‘linear’ about the way DNA functions as a molecule at all.
In the nucleus, DNA appears to form a variety of 3D structures that play pivotal roles in its function. Moreover, we now know that the famous double helix is not the only form in which DNA strands can pair up.
Over the last decade, it has in fact become clear that these DNA structures that don’t follow the rule of classic Watson-Crick pairing of the four letters of the code (A with T, and C with G) have an impact on many different cellular functions.
So, about 60 years after we gained the first insights into the wonders of the very core of biological existence, we are faced with another challenge: understanding the function of odd, atypical 3D DNA structures.
One such structure is called G-quadruplex (G4) DNA. It forms when four G’s in the code (technically termed guanine bases) associate via hydrogen bonds to form a square planar structure – the guanine tetrad. Two or more guanine tetrads can stack on top of each other to form a G-quadruplex.
G4 forms in regions of repetitive DNA that contain stretches of guanines and it has been predicted that in the human genome over 300,000 G4 structures can potentially form although it has been frustratingly difficult to observe these forms in a living cell.
One important region of the human genome that contains such G-rich stretches are telomeres, the ends of DNA molecules whose length regulates aging and are of crucial importance in the transformation of normal cells into cancerous cells.
One potentially G4-related genetic disease is known as ATR-X Syndrome, a rare form of intellectual disability that only affects boys and that is associated with a wide range of physical and mental developmental abnormalities.
The disease is caused by mutations in a protein called ATRX (alpha thalassemia/mental retardation syndrome X-linked), and has been the research focus of Richard Gibbons and Doug Higgs in the MRC Molecular Haematology Unit at the WIMM for over 20 years.
A few years ago, Richard Gibbons and his team showed that ATRX binds to G-rich repetitive sequences in different regions of the genome, including a section of DNA found close to some of the genes involved in producing haemoglobin (the protein complex that allows red blood cells to carry oxygen). If ATR-X is defective, these changes can therefore cause anaemia.
This repetitive region may contain a variable number of G-rich repeats in different individuals. Interestingly, a larger stretch of repeats leads to a greater degree of down-regulation of the adjacent genes, and a more severe case of anaemia.
Based on these results and on more recent findings by the scientific community regarding the importance of G4 DNA, scientists at the WIMM are now working to unravel the mechanisms by which ATRX binds G4 structures, and how mutations in ATRX lead to the symptoms seen in patients with ATRX syndrome.
As often happens in biology, we came across the importance and the many roles of G4 DNA only after we saw the effect of its deregulation in human disease.
This is the starting point to both better understand the predominantly unknown function that 3D DNA structures have in the human genome, as well as investigating new potential targets to fight serious genetic diseases such as ATR-X Syndrome.
Post edited by Bryony Graham, Doug Higgs and Richard Gibbons.