FRANKFURT. Although DNA is tightly packed and protected within the cell nucleus, it is constantly threatened by damage from normal metabolic processes or external stressors such as radiation or chemical substances. To counteract this, cells rely on an elaborate network of repair mechanisms. When these systems fail, DNA damage can accumulate, impair cellular function, and contribute to cancer, aging, and degenerative diseases.

One particularly severe form of DNA damage are the so-called DNA–protein crosslinks (DPCs), in which proteins become attached to DNA. DPCs can arise from alcohol consumption, exposure to substances such as formaldehyde or other aldehydes, or from errors made by enzymes involved in DNA replication and repair. Because DPCs can cause serious errors during cell division by stalling DNA replication, DNA–protein crosslinks pose a serious threat to genome integrity.

The enzyme SPRTN removes DPCs by cleaving the DNA-protein crosslinks. SPRTN malfunctions, for example as a result of mutations, may predispose individuals to develop bone deformities and liver cancer in their teenage years. This rare genetic disorder is known as Ruijs-Aalfs syndrome. Its underlying mechanism remains poorly understood, and there are no specific therapies.

Now a research team led by Prof. Ivan Ðikić from the Institute of Biochemistry II at Goethe University demonstrated that the loss of a functional SPRTN enzyme not only leads to the accumulation of damaged DNA in the cell nucleus. Using cell culture experiment and genetically modified mice they found out that, in addition, DNA from the nucleus also leaks into the interior of the cell, the cytoplasm.

DNA in the cytoplasm is recognized by the cell as a danger signal, as such DNA usually originates from invading viruses or bacteria or from malignant transformation. Cytoplasmic DNA therefore activates defense mechanisms in the cell by initiating the so-called cGAS-STING signaling pathway. Furthermore, the cell releases messenger substances that attract immune cells, leading to chronic inflammation.

The Frankfurt-led research team observed that this chronic inflammatory response is especially pronounced in the mouse embryos and persists in adulthood, particularly in the lung and liver. As a result, the mice died early or showed signs of premature ageing similar to those seen in people with Ruijs-Aalfs syndrome. Blocking the relevant immune response alleviated many of the symptoms.

“Unrepaired DNA-protein crosslinks have broader systemic consequences,” explains Ðikić. “They not only compromise genome stability but also drive chronic inflammation that can significantly influence lifespan.”

The physician and molecular biologist sees potential for the development of therapies: “In addition to Ruijs-Aalfs syndrome, there are other rare genetic diseases in which DNA-protein crosslinks play an important role. With our work, we have laid an important foundation for future therapeutic approaches to these diseases as well. By studying the underlying mechanisms of these rare diseases, we discovered a new link between DNA damage, inflammatory responses, and the lifespan of an organism. This also contributes to the understanding of the biology of ageing.”

Partners in the research project included Goethe University and Johannes Gutenberg University Mainz (Institute of Molecular Biology/Professor Petra Beli and Institute of Transfusion Medicine/Professor Daniela Krause) within the Rhine-Main Universities alliance (RMU), the German Consortium for Translational Cancer Research (DKTK), the German Cancer Research Center (DKFZ), EPFL Lausanne, Charité Berlin and the Universities of Cologne and Split (Croatia).