Mayo Clinic researchers have identified a protein that acts like a traffic controller for DNA, preventing damage during cell division - a discovery that could lead to new cancer therapies, according to a study published in Nature.
"DNA is the code of life. It's critical for how a cell functions, but it's also critical for our own being and defines what we are," says Zhenkun Lou, Ph.D., the Swanson/Schmucker Endowed Professor to Support Health and Cancer Research at Mayo Clinic and the senior author of the new study.
When cells divide, DNA must be copied from one cell to the next - a process called replication. Dr. Lou's research team discovered that a protein called KCTD10 plays a surprising role in protecting DNA during this critical stage. Acting like a built-in sensor, KCTD10 helps shield the DNA replication machinery from damage.
Cells also depend on another key process called transcription, where the cell decodes the DNA to create RNA. That RNA then can be translated into proteins, which are essential for healthy tissues and the body's everyday functions.
The problem is that the different machines that run these two processes - replication and transcription - travel on the same strand of DNA, like a narrow highway. The replication machinery moves faster than the transcription machinery. Therefore, collisions resulting in DNA damage inevitably occur. Researchers did not know how cells communicate to prevent or recover from these collisions until now.
Dr. Lou's research team saw that KCTD10 can sense when a collision is about to occur and act like a traffic controller, triggering a series of responses to prevent it. The protein activates an enzyme called CUL3 that steps in to tell the slower transcription machinery to move aside and allow the replication machinery to pass, avoiding harmful breaks to the DNA. CUL3 and KCTD10 achieve this through a process called ubiquitination that removes the proteins in front of the replication machinery.
It has long been observed that DNA replication and transcription run in the same direction. The findings in this study suggest that KCTD10 may play a significant part in this, shaping the overall organization of the human genome.
Killing cancer cells
"I became interested in the idea that if we can better understand how these processes normally occur, then we can more effectively target cancer cells where these processes malfunction, tipping them over the edge towards cell death," says Jake Kloeber, an M.D.-Ph.D. student and co-lead author of the study. He conducted the study in the Ph.D. component of his dual degree at Mayo Clinic Graduate School of Biomedical Sciences and Mayo Clinic Alix School of Medicine. Kloeber plans to pursue a career as a physician-scientist in radiation oncology.
When KCTD10 is missing, it leads to genomic instability and mutations that can result in tumor formation. Previous research has also shown that developmental delays are linked to the loss of KCTD10.
On the other hand, in cancer cells that lack the protection of KCTD10 because the replication and transcription machinery do not work properly, the missing protein can serve as a biomarker for the vulnerability of these cancer cells.
"We can take advantage of that and attack those cancer cells when they are most vulnerable, which opens a new therapeutic window for us to treat certain types of cancer," says Dr. Lou.
Next steps in this research are identifying which types of cancer are missing this protein and pinpointing ways to target those cancer cells with new or existing cancer drugs.
The research is part of a larger effort at Mayo Clinic called the Precure initiative focused on developing tools that empower clinicians to predict and intercept biological processes before they evolve into disease or progress into complex, hard-to-treat conditions.
Review the study for a complete list of authors, disclosures and funding.
