LMU researchers show that the chemotherapeutic drug azacitidine damages RNA and reveal a possible approach to improve therapies.

Chemotherapeutics are designed to damage cancer cells in a targeted manner – often by targeting their genetic material. The drug azacitidine, for example, has been used for decades to treat two types of blood cancer – acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). The drug had previously been shown to cause DNA damage in cells. A research team led by LMU biochemist Professor Julian Stingele, collaborating with researchers from the group of Professor Sir Steve Jackson from the University of Cambridge, has now discovered that azacitidine also damages RNA.

The integrity of DNA and RNA is essential for every cell. DNA contains the genetic information for proteins, while RNA serves as a working copy of individual genes and is required for the synthesis of proteins. Unlike DNA mutations, RNA damage is not heritable. However, it does trigger a stress response that can be toxic for the cell and lead to cell death.

A mechanism for RNA damage tolerance

“Azacitidine does not work for all patients, and so far it is not known why,” says Carla Engel, doctoral student in the Stingele lab. “Understanding exactly how it works would be crucial to predict which patients will respond well to the drug and which will not.” Azacitidine is incorporated predominantly – around 80 to 90 percent – not into DNA, but into RNA, which causes damage. The researchers have now demonstrated that damage in messenger RNA (mRNA), which transports the blueprints for proteins to ribosomes, blocks protein synthesis. This in turn triggers the so-called integrated stress response that leads to cell death.

“Interestingly, we’ve also discovered that cells possess a certain tolerance toward low levels of RNA damage,” says Dr. Shubo Zhao, former postdoctoral student in the Stingele lab. A protein called RNF25 ensures that the stress response is activated only in the case of damage levels that threaten the cell. If the protein is absent, cells are extremely sensitive to RNA damage. This damage tolerance mechanism thus partly determines how successfully chemotherapy kills cancer cells and could explain why therapies differ in their effectiveness. “The targeted modulation of RNA damage responses could therefore be an interesting approach to improve the outcomes of cancer therapies,” says Julian Stingele.