By taking a closer look at four-stranded versions of DNA inside the genome of human cells, scientists have discovered some potential new avenues for targeted cancer treatments. They found that the quadruple helix structures occur in DNA regions that control genes, especially cancer genes.

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The aim of targeted therapy is to attack cancer cells without affecting healthy cells.

The researchers, from the University of Cambridge in the United Kingdom, report their findings in the journal Nature Genetics.

Targeted cancer therapies are currently the focus of much research and development into new anticancer treatments.

They are an important area of precision medicine – where information about an individual patient’s genes and proteins are used to prevent, diagnose, and treat disease.

A main difference between targeted cancer therapy and standard chemotherapy (chemo) is that most chemo treatments act on all rapidly dividing cells – cancerous and healthy alike.

The aim of targeted therapy is to single out only the cancer cells, without affecting healthy cells.

In order to single out cancer cells as a basis for treatment, researchers have to find features that are either unique to or more common in cancer cells than healthy cells, such as particular molecular pathways or genetic characteristics.

School-level biology teaches us about the familiar two-stranded or double helix structure of DNA, but not many of us know there is another version that has a four-stranded or quadruple helix structure.

Quadruple helix DNA structures are often termed G-quadruplexes because they are especially prevalent in DNA regions rich in guanine (G), one of the four main bases that form the nucleic acids DNA and RNA.

The team behind the new study was the same team that first discovered G-quadruplexes in human cells.

However, at the time, the researchers were not sure exactly where G-quadruplexes were located in the human genome or what they did.

Senior author Shankar Balasubramanian, a professor in the Department of Chemistry and of the Cancer Research UK Cambridge Institute, says there have been several hypothetical suggestions that G-quadruplexes are linked to cancer, and remarks:

“But what we’ve found is that even in non-cancer cells, these structures seem to come and go in a way that’s linked to genes being switched on or off.”

For their study, the researchers used small molecules to tweak pre-cancerous human cells in the lab and a high-throughput sequencing approach to search for G-quadruplexes.

The team located around 10,000 G-quadruplexes, mostly in DNA regions that control gene behavior such as switching them on or off – particularly genes linked to cancer.

Lead author Dr. Robert Hansel-Hertsch, a postdoctoral research associate in Prof. Balasubramanian’s group, says they found the G-quadruplexes in regions of the genome where transcription factors control the fate and function of cells.

“The finding that these structures may help regulate the way that information is encoded and decoded in the genome will change the way we think this process works,” he suggests.

The team thinks G-quadruplexes may play a similar role to epigenetic marks – small chemical tags that affect how the associated region of DNA is interpreted and how genes are switched on and off.

The researchers suggest G-quadruplexes could be a target for early diagnosis and treatment of cancer in precision medicine.

Prof. Balasubramanian says they have been wondering why, unlike non-cancer cells, certain cancer cells appear to respond more readily to small molecules that target G-quadruplexes, and suggests:

“One simple reason could be that there are more of these G-quadruplex structures in pre-cancerous or cancer cells, so there are more targets for small molecules, and so the cancer cells tend to be more sensitive to this sort of intervention than non-cancer cells.”

“It all points in a certain direction,” he concludes, “and suggests that there’s a rationale for the selective targeting of cancer cells.”

Figuring out the fundamental processes that cancer cells use to switch genes on and off could help scientists develop new treatments that work against many types of the disease.”

Dr. Emma Smith, science information manager, Cancer Research UK

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