Scientists Are Just Beginning to Understand Mysterious DNA Circles Common in Cancer Cells

Scientists Are Just Beginning to Understand Mysterious DNA Circles Common in Cancer Cells

For years, researchers weren’t exactly sure what to make of these extra loops of genetic material . That’s quickly changing.
Credit...Wu et al, Nature, 2019
There’s no image in biology more iconic than our chromosomes — all 23 pairs of DNA bundles arrayed in a genetic lineup. But in a surprising number of cases, this picture leaves out something very important.
In some cells, extra circles of DNA float alongside the regular chromosomes. Scientists first noticed this so-called extrachromosomal DNA five decades ago. But for years they weren’t exactly sure what to make of it.
New research is now focusing on those mysterious loops. They are surprisingly common in cancer cells and play a bigger role in many types of cancers than was previously recognized. Healthy cells can carry smaller circles of their own. These DNA circles also may affect how our bodies work, and may even be linked to aging or diseases other than cancer.
“I think we’re just opening our eyes up,” said Birgitte Regenberg, a biologist at the University of Copenhagen who has pioneered methods for detecting these circles. She is co-organizing the first meeting on circular DNA, to be held in Berlin in January.
The existence of these circles first became apparent in the 1960s. Cancer researchers added stains to tumor cells to highlight the cells’ chromosomes. Those studies revealed that cancer cells acquire mutations that drive them to grow aggressively.
But the scientists noticed something in the cells beyond the 23 pairs of chromosomes: In some of them, sitting alongside the chromosomes, were little clumps of DNA.
Those clumps went by many names over the years, such as double minutes and extrachromosomal DNA. Most scientists considered them rare and unimportant, largely because they lacked the tools to detect them. The DNA circles lurked unseen in the crowded neighborhood of chromosomes. Sequencing DNA gave no hint that the DNA in question came from a separate circle, rather than from a chromosome.
Since then, researchers like Dr. Regenberg have invented techniques to examine the DNA in those circles. Other scientists have figured out how to highlight the circles with glowing proteins, and even how to prepare them for a close-up portrait under high-powered microscopes.
“They look like SpaghettiOs,” said Paul Mischel, a cancer biologist at the University of California at San Diego.
As a result of this work, Dr. Mischel and other researchers have a better understanding of these circles of DNA.
“Our analysis indicates that they’re present in half of cancer types and in a quarter of the cancer samples we study,” said Howard Chang, a geneticist at Stanford University. “So it’s pretty common.”
In a paper published Wednesday in the journal Nature, Dr. Chang, Dr. Mischel and their colleagues reported that the DNA on these circles behaves differently than the DNA on chromosomes. For one thing, the genes are more active — “order of three to five times more” active, Dr. Chang said.
The DNA in chromosomes is wound into tight spools. This careful organization ensures that only certain genes are active, and the rest stay silent. But when a cell accidentally copies DNA from a chromosome into a circle, those safeguards are lifted, Dr. Chang said. “The DNA becomes much more accessible to the cell’s machinery.”
Researchers are also finding that cancer cells may carry dozens or hundreds of copies of the same circle. It’s not yet entirely clear how the circles multiply. Part of the answer is that these circles of DNA don’t obey the same rules that chromosomes do.
A dividing cell goes through an orderly process to make a new set of chromosomes. Molecular hooks then drag the two sets of chromosomes to opposite ends of the cell, which then splits down the middle.

DNA circles avoid those hooks. How many circles end up in each of the two new cells seems to be random. The cells may split the DNA circles evenly, or one may end up with more than the other. In some cases, one cell hits the jackpot and inherits them all.

Credit...Wu et al, Nature, 2019

Dr. Mischel and other researchers have found evidence that a large inheritance of circles can speed up a cell’s growth. As this lottery plays out with each new cell division, it may allow cancers to rapidly become aggressive.

DNA circles can also slip back into chromosomes, according to a new study led by Anton G. Henssen, a pediatric oncologist at Charité University Hospital Berlin and the Max Delbrück Center of Molecular Medicine. Dr. Henssen thinks that the circles may endow nearby genes with their overdrive, which may lead cells to become more dangerous.

“It’s a very powerful vehicle for cancer evolution,” said Dr. Henssen, a co-organizer of the upcoming meeting in Berlin.

Dr. Chang, Dr. Mischel and their colleagues have started a company called Boundless Bio to look into potential treatments based on their research.

“If you can clear these circles, it’s a way to attack cancer,” said Dr. Anindya Dutta, a molecular biologist at the University of Virginia School of Medicine, who is not involved in the company.

DNA circles aren’t found only in cancer cells. Healthy cells have them, too, studies have shown. In one of these studies, published last year, Dr. Regenberg and her colleagues obtained samples of blood and muscle from 16 people. They extracted DNA from the material and used chemicals to dissolve away the DNA on the chromosomes. When the team analyzed the DNA that remained, they found the signature of about 100,000 different kinds of circles.

There seem to be stark differences between the DNA circles in healthy and diseased cells. In cancer cells, the circles may contain a million base pairs of DNA or more, Dr. Chang and his colleagues found. In contrast, the DNA circles in healthy cells are typically much smaller, containing under 25,000 base pairs, and usually just a few hundred. (The entire human genome contains about three billion base pairs.)

It may be that bigger loops of DNA pose a greater threat of cancer, because they are large enough to house genes that could help a cell grow faster. A small circle may not be long enough to really matter. “They don’t have the real estate to contain a whole gene,” Dr. Dutta said.


But Dr. Dutta thinks that some small circles may still have an impact. He and his colleagues have shown that circles that are too small to encode a protein can still encode small, potent molecules called microRNAs. Those molecules can act like switches, turning off other genes.

As tantalizing as such findings are, they don’t reveal whether small circles of DNA have an influence on our health. For instance, many different kinds of small DNA circles have been found in healthy cells, but researchers don’t know how common they are. Maybe they are too rare to make a difference.

But Dr. Regenberg says we shouldn’t write them off. She expects that the effect of DNA circles may extend far beyond cancer, which has drawn most of the scientific attention thus far.

“It’s been very cancer-centered,” she said. “It’s like when a horse has blinders: The blinders focus the science, but they also prevent some things from being understood.”


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