Nucleolar DDR Pathways May be Key to Stopping Cancer’s Protein Factories

Scientists are working on a new strategy to tackle cancer, a disease that affects millions of people every year. According to a paper published in Trends in Biology, researchers from the University of North Carolina at Charlotte have uncovered more about nucleolar DNA damage response (DDR) pathways. Their findings highlight six mechanisms that cells use to repair DNA damage, including one that was published five months ago in Nucleic Acids Research by the same authors.

The team’s work began in 2007 when they first published a paper in Nature detailing how to help repair mismatched base pairs when copying ribosomal DNA. By studying these mechanisms, researchers can target cancer, which relies on ribosomal DNA to make the proteins they need to attack the human body.

The review paper focuses on six distinct perspectives on how nucleolar DDR checkpoint pathways are activated by different stresses or by liquid-liquid phase separation (LLPS). According to Shan Yan, the main author of the study, the whole purpose of their work is to bring attention to scientists in this relatively new field and trigger more research.

Yan discovered that a protein called APE1 could locate the nucleolus within a cell and could also pop up these liquid tents to do work, which led to his investigation into these pathways and ultimately to the review paper. “APE1 acts like a GPS or a first responder and says there’s a problem here, we need a police car, a medic, and others to come and be concentrated here,” Yan explains.

The first four mechanisms occur inside the nucleolus, while the last two use a new cellular process called liquid-liquid phase transition, which won the 2023 Breakthrough Prize in Life Sciences. In the process, proteins pop up their own liquid tents to do their work instead of staying inside a room.

A drug targeting the second mechanism in the paper is already underway in a Phase I clinical trial. If cancer cells can’t heal these “glitches”, they can’t make new factories, and hence they can’t make new proteins. Researchers like Yan will continue to better define these mechanisms, while more applied scientists can then use those mechanisms as points of attack in the war on cancer.

Yan concludes, “This is an exciting and emerging area. By testing this idea, and if the clinical trial is successful, then these mechanisms will be tickets into new clinical trials and treatments.” These findings open up new opportunities for basic researchers and oncologists to look into new areas for cancer therapeutics.