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'Doughnut-Shaped' DNA Makes Cancer More Aggressive

This image taken by a scanning electron microscope shows chromosomes (blue arrow) and ring-shaped DNA (orange arrow)
This image taken by a scanning electron microscope shows chromosomes (blue arrow) and ring-shaped DNA (orange arrow).
(Image: © Image courtesy of Paul Mischel, UC San Diego)

Cancer cells may owe some of their destructive nature to unique, "doughnut-shaped" DNA, according to a new study.

The study, published today (Nov. 20) in the journal Nature, found that, in some cancer cells, DNA doesn't pack into thread-like structures like it does in healthy cells —  rather, the genetic material folds into a ring-like shape that makes the cancer more aggressive.

"DNA conveys information not only in its sequence but also in its shape," said co-senior author Paul Mischel, a professor of pathology at the University of California at San Diego. 

As you may remember from biology class, most of our DNA is packed tightly inside cell's nuclei in structures known as chromosomes. Almost all cells have 23 pairs of chromosomes, each of which consists of about 6 feet (1.82 meters) of DNA tightly wound around groups of proteins that serve as a scaffold. 

Related: Code of Life: Photos of DNA Structures

This jam-packed structure allows for some genes to be accessible by the molecules that "read" and  carry out the genetic instructions, while other genes to stay hidden. What results is highly regulated machinery that keeps the cell from carrying out unwanted genetic instructions and from replicating (creating new "daughter cells") in an erratic way.

"Everything we've learned about genetics says that changes [in cells] should be slow," Mischel told Live Science. But years ago, Mischel and his team found that in a certain type of brain cancer called glioblastoma, tumors "seemed to be able to change at a rate that just didn't make any sense." The tumor cells, as they divided into daughter cells, seemed to be somehow amplifying the expression of oncogenes — genes that can transform a regular cell into a cancerous one.

It turned out that that some of these amplified copies of oncogenes had "untethered themselves from chromosomes," Mischel said. Having broken loose from the chromosomes, they were hanging out on other pieces of DNA inside the cell, according to a paper the authors published in the journal Science in 2014. They then found that these "extrachromosomal" pieces of DNA (ecDNA) actually occur in nearly half of human cancers but have rarely been detected in healthy cells, a finding the authors reported in a paper published in the journal Nature in 2017.

In this new study, they figured out why ecDNA is so robust. A combination of imaging and molecular analysis revealed that these pieces of DNA are wrapped around proteins in a ring shape, similar to the circular DNA found in bacteria. 

This ring shape makes it much easier for the cell's machinery to access a slew of genetic information — including the oncogenes — so that it can quickly transcribe and express them (for example, instruct a healthy cell to turn cancerous), Mischel said. This easy accessibility allows tumor cells to generate large amounts of tumor-promoting oncogenes, evolve quickly and adapt easily to a changing environment. 

What's more, the researchers found that in contrast to healthy cells that divide out their genes to their daughter cells in a regular and expected way, these cancer cells distribute their ecDNA in random ways. It's like "a factory for pumping tons and tons of oncogenes," leading to some daughter cells receiving multiple copies of oncogenes in a single cell division, Mischel said.

"This is a very exciting study," said Feng Yue, director of the Center for Cancer Genomics at Northwestern University Lurie Cancer Center, who was not involved with the research. "This work represents a conceptual advancement of how ecDNA contributions to oncogenesis in human cancer."

Mischel, and some of the other study authors are co-founders of Boundless Bio Inc., a company that's researching ec-DNA based therapies. Study co-author Vineet Bafna is also a co-founder and has an equity interest in the company Digital Proteomics, but the authors claim that neither company was involved in this research.

Originally published on Live Science.