Researchers discover protein that doubles down on cancer

Volume 6, Issue 1, 2017

Summary

The cyclin A2 protein regulates the cell cycle and plays a role in fixing DNA replication errors.

Photograph of Jan van Deursen, Ph.D.

Jan van Deursen, Ph.D.

Photograph of Arun Kanakkanthara, Ph.D.

Arun Kanakkanthara, Ph.D.

The normal human cell cycle of replication can introduce errors, but the safeguards in DNA automatically repair most of those errors. When that repair system breaks down, though, cancer can develop from resulting mutations.

Mayo Clinic researchers have discovered that the protein that regulates the cell cycle, called cyclin A2, does double duty. In addition to its role as an RNA-binding protein to coordinate DNA duplication during cell division, cyclin A2 also plays a role in establishing the machinery that fixes cancer-causing DNA replication errors.

The researchers, who published their findings in an article in the Sept. 30, 2016, issue of Science, identified cyclin A2 as a first example of a protein that binds to RNA to control the production of another single protein, Mre11, a key DNA repair protein.

"Cyclins constitute a family of proteins that all living organisms possess to orchestrate ordered progression through the cell division cycle," said Jan van Deursen, Ph.D., a researcher at Mayo Clinic's campus in Rochester, Minnesota, and senior author of the published report.

"Most family members were discovered 25 to 30 years ago and thought to uniquely function in the sequential activation of specific cyclin-dependent kinases at different stages of the cell cycle clock," said Dr. van Deursen, who is also a professor of biochemistry and molecular biology in the Mayo Clinic College of Medicine and Science. "Disruption or deregulation of the cell cycle is a common cause in the development of cancer, so researchers have been interested in understanding this process in the greatest detail in the hope to use this knowledge to develop new medicines to treat human cancers."

Investigation of cyclin A2's functions in living organisms posed a unique technical hurdle for the Mayo Clinic research team because of the crucial importance of this protein for survival of cells engaging in cell division.

The normal approach for this kind of research would involve making genetically altered knockout mice with cyclin A2 removed so that the effects of this omission could be detected and linked to the protein's function. But in this case, because the function of the protein is essential for cell division, none of the mice survived; the genetic alteration was lethal.

To overcome this setback, the Mayo Clinic researchers prepared a second set of genetically modified mice, this time controlling the modification so that enough of the protein was available to keep them alive. Although the mutant mice looked normal, they were prone to cancer.

Experiments designed to decipher the underlying causes revealed that cyclin A2 harbors a unique functional unit that allows it to bind to the gene transcripts of Mre11 to usher them to ribosomes, which are particles specialized in translating transcripts into proteins.

"This new cyclin A2 property is essential to make sufficient Mre11 protein at the start of DNA duplication to repair cancer-causing errors that inevitably happen during this process," said Arun Kanakkanthara, Ph.D., a senior research fellow in the Division of Medical Oncology at Mayo Clinic's campus in Rochester, Minnesota, and lead author of the Science article. "The expectation is that cyclin A2 is a founding member of a new family of RNA-binding proteins whose own expression is tightly coordinated with another protein through protein translation mechanism."