While the iconic double helix is the most famous shape DNA can take, it is not the only one. Our genetic material can fold into a variety of complex forms, one of which is the quadruplex. Also known as a G-quadruplex (G4), this structure is a four-stranded arrangement found in both DNA and RNA. If the double helix is a twisted ladder, a quadruplex is like an intricate knot in our genetic code. This is a naturally occurring feature within our cells, formed in specific areas of our genome.
The Unique Structure of a Quadruplex
A quadruplex structure forms in regions of DNA or RNA with a high concentration of the genetic base guanine. This prevalence of guanine gives the structure its common name, G-quadruplex. The formation relies on four guanine bases forming a square-like plate known as a G-quartet. This unit is held together by Hoogsteen hydrogen bonds, which differ from the Watson-Crick bonds that pair up the rungs of the double helix.
For a stable quadruplex to form, multiple G-quartets stack on top of one another, creating a channel through the center of the structure. The stability of this assembly depends on a positively charged ion, often potassium, which sits in the central channel between the G-quartet layers. This ion coordinates with the guanine bases, acting as a stabilizing scaffold that holds the stacked plates together.
This four-stranded structure is different from the two-stranded double helix. Instead of two strands twisting in a spiral, the quadruplex involves one or more strands folding to create a compact shape from stacked guanine squares. This stable fold can be formed from a single strand of DNA or RNA, or by the interaction of two or even four separate strands. This structural diversity allows quadruplexes to perform a wide range of functions within the cell.
Biological Roles and Locations
Quadruplex structures are not randomly scattered but are found in specific, functional locations within the genome. One of their most well-documented sites is in telomeres, the protective caps at the ends of our chromosomes. Telomeres consist of long, repetitive DNA sequences rich in guanine, making them ideal for G-quadruplex formation. These structures help protect the chromosome ends from being degraded during cell division, contributing to genomic stability.
Beyond the chromosome ends, quadruplexes are also enriched in the promoter regions of genes. A gene’s promoter is a segment of DNA that controls when and how a gene is turned on or off. By forming a stable structure in a promoter, a quadruplex can act as a physical roadblock, preventing cellular machinery from accessing the gene. This process acts as a “dimmer switch” for gene expression, reducing the rate of transcription. Over 40% of human gene promoters contain sequences capable of forming these structures, suggesting a widespread regulatory role.
The formation and dissolution of these structures are dynamic processes. Specialized proteins known as helicases can unwind quadruplexes, allowing transcription to proceed when needed. This interplay between formation and unwinding allows the cell to control the activity of thousands of genes, highlighting their importance in normal cellular processes.
Implications for Disease and Medicine
The regulatory functions of quadruplexes are also linked to disease when their balance is disrupted, a connection particularly strong in cancer research. G-quadruplex-forming sequences are often found in the promoter regions of oncogenes—genes that can cause cancer when overactive. Oncogenes like c-MYC, which helps control cell growth, contain these structures, and their stabilization can lead to uncontrolled cell division.
The increased presence of quadruplexes in cancer cells makes them an attractive therapeutic target. The strategy is to exploit their function rather than destroy them. Scientists are developing small-molecule drugs that recognize and bind to G-quadruplexes, acting like a molecular clamp to lock the structure. By over-stabilizing the quadruplex in an oncogene’s promoter, the drug jams the gene in the “off” position, halting the production of cancer-promoting proteins.
This approach is selective, as it targets a feature more abundant in cancer cells. Beyond cancer, research is uncovering the role of quadruplexes in other conditions. An imbalance in G-quadruplex formation may contribute to cellular aging and some neurodegenerative diseases, like Alzheimer’s and amyotrophic lateral sclerosis (ALS). In these cases, abnormal quadruplex stability could interfere with protein production or contribute to genomic instability, opening new avenues for treatment.