Four-stranded DNA a new research field

Four-stranded DNA has been discovered in association with cancer-driving genes. Nasim Sabouri is studying its function in cells, and hopes to develop new and more effective cancer drugs.

Nasim Sabouri

PhD, Medical Chemistry

Wallenberg Academy Fellow 2015

Institution:
Umeå University

Research field:
The function of four-stranded DNA in cells

The human genome is usually formed as a double helix. At first, the researchers who discovered four-stranded DNA thought they had found artifacts from their own experiments.

Researchers have recently begun to realize that DNA can assume other configurations, like the four-stranded structure, and that they have been conserved throughout evolution. This suggests they may perform important functions in the cell.

Stabilizing four-stranded DNA

The DNA strand consists of smaller units, known as nucleotides, which include a nitrogen base: cytosine (C), guanine (G), adenine (A) or thymine (T). The sequence of the nitrogen bases determines which of the body’s proteins will be built.

Sabouri, researching at Umeå University, is studying a four-stranded structure formed when guanine bases from the same or different DNA strands interact with one another. It is called G-quadruplex (G4), and is often found near DNA regions that turn gene activity on or off. It is also found in telomeres, for example, which are located at the end of chromosomes.

“It is believed that four-stranded DNA is formed inside the cell, but this has been difficult to prove. This is why development in this field has stalled. But there are now more and more data suggesting they really are present in the cell,” Sabouri explains.

G4-DNA has been found both in HIV and in human papillomavirus (HPV), and also in association with cancer-driving genes. This makes the G4 structure a potential target for both antiviral drugs and cancer preparations.

“It is interesting to study how G4 may be linked to certain diseases. If we understand the basic functions of the G4 structure, it will help us to understand how cancer is caused. Then we will also be able to attack the cancer cells to stop them growing.”

Sabouri and her colleagues have two strategies for analyzing G4 in greater detail. First they will be trying to find medicine-like compounds that can stabilize the structure.

“If the G4 structures retain their form for a substantial portion of the cell’s lifecycle, it will be easier for us to study how they work. We will be able to see how gene regulation is impacted, for example,” Sabouri says.

The next step will be to isolate and characterize proteins that bind to G4-DNA.

“When we’ve identified specific proteins interacting with G4 structures inside the cell, we will be able to examine the cellular mechanisms to which they are connected, and then understand which of them cause disease.”

Modeling with yeast

DNA sequences that form G4 structures are found in the DNA of virtually all organisms – including yeast, which is the model system the research team is using.

“Yeast is a single-celled organism that grows rapidly. It duplicates in 90 minutes. Yeast is also easy to genetically modify. Its chromosomes are highly similar to those in human cells, which are much harder to work with.”
Eventually, she hopes to be able to move on from yeast model experiments to higher cells, although much still remains to be done.

“Every time we start something new we are among the first in the world, since the field has been so little researched. It’s really exciting,” Sabouri enthuses.

“It is a great privilege for me as a young researcher to be given the chance to set up a research team and commit to projects that are a little riskier and take more time.”

Sabouri was born in Iran, and moved to Sweden at the age of nine. She liked biology and chemistry during her high school years in Täby, north of Stockholm, and applied for a place on the molecular biology program at Stockholm University.

“I had a friend in the volleyball team whose dad was a professor at Karolinska Institutet. I was able to go there in the evenings and on weekends to help in the lab. It was fun,” Sabouri recalls.

Her next step was the graduate school in biomedicine in Umeå, northern Sweden. A project on DNA synthesis brought her into contact with a research team, which she later joined as a PhD student. She gained her PhD in 2008, with a thesis describing how the enzyme DNA polymerase can bypass damaged DNA during DNA replication.

Sabouri wanted to learn more about the chromosome regions that are difficult to replicate, so she applied for a position as a postdoc at Princeton University, New Jersey in the U.S., under a professor well known in the field.

A few years later she returned to Umeå, where she was able to set up her own research team. Her admission as a Wallenberg Academy Fellow in 2015 has enabled her to recruit new members to her team. She is now working with two PhD students, three postdocs and a research engineer.

“The atmosphere changed completely as the team grew. Everyone has their specialty, and we learn a lot from each other. We get more results and make faster progress,” Sabouri comments.

Text Carin Mannberg-Zackari
Translation Maxwell Arding
Photo Magnus Bergström