HMN 2026: how cells maintain their DNA could shield key healthy cells from chemotherapy side effects

A new study conducted by scientists at the University of Sheffield in collaboration with researchers from UT Southwestern Medical Center in the U.S. has found a protein that could help guide which cells chemotherapies target. The findings, published in Molecular Cell, open up a promising new avenue for research into treatments that can aggressively target tumors while preserving patients’ long-term quality of life.

The researchers used cells extracted from mice (in vitro) to look at one branch of chemotherapies known as TOP2 poisons, which target the enzymes that enable cancer cells to rapidly divide and multiply. The enzymes cut, untangle and then stitch the DNA of cancer cells back together in order to form a new cell. TOP2 chemotherapies exploit this by trapping the enzymes mid-cut. This leaves behind catastrophic DNA breaks that force the cancer cells to self-destruct.

However, these drugs cannot differentiate between a tumor and healthy tissue. Vital, nondividing cells, such as neurons in the brain and cardiomyocytes in the heart, also rely on these enzymes to function. These healthy cells are also destroyed by the chemotherapy treatment, which causes severe side effects for the patient, as the cells cannot be replaced.

A crucial difference in healthy cells

Now, the team has identified a way to exploit a subtle difference between cancer cells and healthy cells to prevent the destruction of vital cells.

While rapidly dividing cancer cells use two variations of this enzyme, TOP2A and TOP2B, healthy, nondividing cells rely exclusively on the TOP2B variant. Selectively targeting the TOP2A variant could prevent toxicity to these healthy cells.

HSF1 helps spare healthy tissue

The researchers revealed that a stress-response protein called HSF1 acts as a highly specific regulator for the activity of these enzymes. Using a nanoscale imaging technique called atomic force microscopy (AFM), the team at the University of Sheffield was able to watch these enzymes bind directly to DNA. They found that HSF1 enhances the binding of TOP2B to DNA, but doesn’t interact with TOP2A.

The team at UT Southwestern then demonstrated that by introducing an HSF1 inhibitor alongside TOP2 chemotherapy, they could drastically reduce the drug’s toxic impact on healthy, nondividing cells. Crucially, because cancer cells still use the TOP2A variant to multiply, the chemotherapy retained its full capacity to destroy the tumor.

Testing the combination in mice

Dr. Thomas Catley, postdoctoral research associate at the University of Sheffield’s School of Chemical, Materials and Biological Engineering, said, “It is incredible to be able to see how these proteins cling to DNA with nanometer precision. Our advanced imaging methods and analysis techniques are allowing us to begin to understand how the many different proteins in our cells interact with each other and the genome. From this, we hope to discover new ways of treating cancer effectively.”

Ram Madabhushi, associate professor at UT Southwestern who led the research, said, “It is intriguing that cells have a way to preferentially regulate TOP2B over TOP2A in this manner. We are currently testing whether combination therapy with HSF1 inhibitors can protect mice from the secondary toxicity of chemotherapy with TOP2 poisons.”

The content is provided for information purposes only.