Fatal error: The failure of the repair enzyme SPRTN in these cultured cells leads to fatal errors in cell division, e.g. by distributing the chromosomes (red) to three daughter cell nuclei instead of two (arrow). Green: Cell division apparatus/cytoskeleton.
Image Credit: Institute of Biochemistry II, Goethe University Frankfurt
Scientific Frontline: "At a Glance" Summary
- Main Discovery: The failure of the DNA repair enzyme SPRTN not only causes genetic damage accumulation but also leads to nuclear DNA leaking into the cytoplasm, which triggers a chronic, aging-accelerating inflammatory response.
- Methodology: Researchers led by Prof. Ivan Ðikić utilized cell culture experiments and genetically modified mice to observe the physiological effects of SPRTN deficiency, specifically monitoring DNA distribution and immune signaling pathways.
- Key Data: In SPRTN-deficient models, chromosomes were observed distributing to three daughter cells instead of two; the resulting chronic inflammation was particularly pronounced in mouse embryos and persisted into adulthood, notably in the lungs and liver.
- Significance: This study establishes a critical link between DNA-protein crosslinks (DPCs), the cGAS-STING immune signaling pathway, and systemic aging, explaining the pathology of the rare hereditary disorder Ruijs-Aalfs syndrome.
- Future Application: Findings suggest that blocking specific immune responses triggered by cytoplasmic DNA could serve as a therapeutic strategy for Ruijs-Aalfs syndrome and other conditions driven by inflammation-associated aging.
- Branch of Science: Molecular Biology and Immunology
- Additional Detail: The cytoplasmic DNA is misidentified by the cell as a pathogen (like a virus), activating defense mechanisms that drive the systemic inflammation responsible for the premature aging phenotype.
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| SPRTN protects the DNA like a helmet by reparing DNA-protein crosslinks. Illustration Credit: Anne-Claire Jacomin, Goethe University Frankfurt |
If severe DNA damage is not repaired, the consequences for the health of cells and tissues are dramatic. A study led by researchers at Goethe University Frankfurt, part of the Rhine-Main University Alliance, shows that the failure of a key DNA repair enzyme called SPRTN not only results in genetic damage, but also triggers chronic inflammatory responses that accelerate aging and lead to developmental abnormalities. The findings shed light on the rare hereditary disorder of Ruijs-Aalfs syndrome and may open new avenues for therapeutic intervention.
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 is 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 because 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 experiments 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 like 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."
Additional information: 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).
Published in journal: Science
Title: DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
Authors: Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, Tsung-Lin Tsai, Thorsten Mosler, Rubina Kazi, Rajeshwari Rathore, Jorge Andrade, Marina Hoffmann, Giulio Giuliani, Anne-Claire Jacomin, Raquel S. Pereira, Elias Knop, Laurens Wachsmuth, Petra Beli, Koraljka Husnjak, Manolis Pasparakis, Andrea Ablasser, Daniela S. Krause, Michael Potente, Stamatis Papathanasiou, Janos Terzic, and Ivan Dikic
Source/Credit: Goethe-Universität Frankfurt
Reference Number: mbio013026_01