Two important functions of the protein RTEL1 during cancer cell division could help pinpoint new cancer treatments, researchers report.

One of the body’s most important processes is cell division, which occurs throughout life. Normal cells only have a limited number of divisions, while in cancer cells the cell division goes awry and is uncontrollable.

Therefore, researchers are working to identify the proteins that play key roles in the cell division of human cells.

The new study shows that this protein—called RTEL1—plays an important role in both S-phase and mitosis.

TWO KEY FUNCTIONS IN CANCER CELL DIVISION

“We discovered RTEL1 has two key functions. In the S-phase, RTEL1 can prevent damaging clashes between the processes of DNA replication and transcription (when RNA is made), which otherwise can cause DNA damage and chromosome instability,” says Ying Liu, associate professor at the Center for Chromosome Stability (CCS) in the cellular and molecular medicine department at the University of Copenhagen.

“It does this by ‘ironing out’ certain unusual structures that can form between DNA and RNA called R-loops. The second feature is that RTEL1 promotes a process called MiDAS, which is very common in cancer cells and happens in mitosis.”

MiDAS stands for “mitotic DNA synthesis” and occurs at the early stage of mitosis. This process was discovered at the CCS in 2015 in a study professor Ian Hickson led.

“Our earlier data showed that cancer cells utilize this unusual form of DNA replication far more often than normal cells, because cancer cells have a lot of ‘replication stress’ in S-phase due to the cell division cycle being perturbed by the over-activity of cancer-causing genes called oncogenes,” says Hickson.

MiDAS helps cells to finish DNA replication that is not completed in S-phase.

“If MiDAS cannot take place, it leads to cell death or mutations in the surviving cells. In the case of cancer, this means that the cancer cell has the potential to become even more abnormal due to the new mutations,” Liu explains.

In the new study, which is a continuation of the previous findings in the CCS, the researchers have primarily done tests on different types of cancer cells including bone, cervical, and colon cancer.

A SURPRISING ROLE
It was a surprise to the researchers to see how big a role the RTEL1 protein plays in cell division.

“We were investigating which proteins help cancer cells to use MiDAS. And then this protein, RTEL1, came up, which was a surprise. We did not expect it had such a big effect,” says Liu.

“We believe that this RTEL1 function is critical for any cancer cells that rely on MiDAS, which is more than 80% of the known cancer types based on our knowledge. Therefore, we can use this to design drugs to inhibit RTEL1 and hopefully selectively kill cancer cells.”

Their next step will be to investigate how RTEL1 performs its two roles and whether they are connected. They will also investigate exactly how RTEL1 promotes MiDAS in mitosis.

The study appears in Nature Structural & Molecular Biology. Additional researchers from the University of Copenhagen and Memorial Sloan-Kettering Cancer Center in New York contributed to the work.

Supported for the work came from, among others, the Danish National Research Foundation, the Nordea Foundation, the NIH, and the European Commission.

Source: University of Copenhagen

Original Study DOI: 10.1038/s41594-020-0408-6