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"Donut-Shaped" DNA Makes Cancer More Aggressive



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

The study, published today (November 20) in the journal Nature, found that some cancer cells, DNA do not pack into thread-like structures as in healthy cells – rather, the genetic material folds into a ring-like shape that makes cancer more aggressive.

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

As you may remember from the biology class, most of our DNA is packed tightly inside the nuclei of the cell in structures known as chromosomes. Almost all cells have 23 pairs of chromosomes, each consisting of about 1

.82 meters of DNA tightly wrapped around groups of proteins that act as a scaffold.

Related: Life Code: Photos of DNA Structures

This pickled structure allows some genes to be available with the molecules that "read" and execute the genetic instructions, while other genes to keep hidden. What results are highly regulated machines that prevent the cell from carrying out unwanted genetic instructions and from replicating (creating new "daughter cells") in an unpredictable way.

"Everything we have learned about genetics says that changes [in cells] should be slow," Mischel told Live Science. But many years ago, Mischel and his team found that tumors "seemed to change in a certain type of brain cancer, called glioblastoma, that just couldn't understand." The tumor cells, which they split into daughter cells, seemed to somehow enhance the expression of oncogenes – genes that can turn a normal cell into a cancerous form.

It turned out that some of these enhanced copies of oncogenes had "disconnected from chromosomes," Mischel said. After detaching from the chromosomes, they hung on other pieces of DNA inside the cell, according to a paper published by the authors in the journal Science 2014. They then found that these "extrachromosomal" portions of DNA (ecDNA) actually exist in Almost half of human cancers, but rarely found in healthy cells, the authors noted in an article published in the journal Nature 2017.

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

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

In addition, unlike healthy cells that divide their genes into their daughter cells in a regular and expected manner, these cancer cells randomly distribute their ecDNA. It's like "a factory for pumping tons and lots of oncogenes," which leads some daughter cells to get 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's Lurie Cancer Center, who was not involved in the research. "This work represents a conceptual development of how ecDNA contributes to oncogenesis in human cancer."

Mischel, and some of the other study authors, are the founders of Boundless Bio Inc., a company that researches oak-DNA-based therapies. Student co-author Vineet Bafna is also one of the founders and has an equity stake in the company Digital Proteomics, but the authors claim that no company was involved in this research.

Originally published on Live Science .


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