New Insights into Ruijs-Aalfs Syndrome: Unveiling the Role of SPRTN and Chronic Inflammation

A research team at Goethe University Frankfurt has identified a new mechanism underlying Ruijs-Aalfs syndrome, a rare genetic disorder characterized by bone deformities and liver cancer.

The study highlights how the malfunction of the DNA repair enzyme SPRTN leads to the accumulation of DNA-protein crosslinks (DPCs), subsequent chronic inflammation, and accelerated aging, providing insights into potential therapeutic directions.

Understanding DNA Damage and Repair

DNA within the cell nucleus is consistently exposed to damage from metabolic processes and external stressors. Cells possess complex repair mechanisms to counter this damage. When these mechanisms fail, DNA damage can accumulate, potentially impairing cellular function and contributing to conditions such as cancer, aging, and degenerative diseases.

DNA-protein crosslinks (DPCs) represent a form of DNA damage where proteins attach to DNA. These DPCs can result from factors like alcohol consumption, exposure to aldehydes, or errors by DNA replication and repair enzymes.

They can hinder DNA replication during cell division, thereby compromising genome integrity.

SPRTN and Ruijs-Aalfs Syndrome: A Critical Connection

The enzyme SPRTN is crucial for removing DPCs by cleaving these crosslinks. Malfunctions in SPRTN, often due to mutations, are associated with Ruijs-Aalfs syndrome.

This rare genetic disorder is characterized by symptoms such as bone deformities and liver cancer, typically manifesting in adolescence or teenage years. Specific therapies for the syndrome are currently unavailable, and its exact mechanisms have been largely unclear.

Key Findings: The Mechanism Unveiled

A research team led by Professor Ivan Đikić at Goethe University conducted experiments using cell cultures and genetically modified mice. Their findings demonstrate that a loss of functional SPRTN not only causes damaged DNA to accumulate within the cell nucleus but also leads to this nuclear DNA leaking into the cell's cytoplasm.

This cytoplasmic DNA acts as a danger signal, activating the cGAS-STING signaling pathway. This activation, in turn, prompts the release of messenger substances that attract immune cells, resulting in a chronic inflammatory response.

The research team observed this chronic inflammatory response to be particularly pronounced in mouse embryos and persistent into adulthood, especially in the lungs and liver. Consequently, the affected mice experienced premature death or exhibited signs of premature aging, mirroring symptoms observed in individuals with Ruijs-Aalfs syndrome. The study also noted that suppressing the associated immune response significantly alleviated many of these symptoms in the mouse models.

Paving the Way for Future Therapies

Professor Đikić stated that unrepaired DPCs have systemic consequences, affecting genome stability and driving chronic inflammation that impacts lifespan.

This research provides a foundation for developing future therapeutic approaches for Ruijs-Aalfs syndrome and other genetic diseases involving DPCs. It also enhances the understanding of the connection between DNA damage, inflammatory responses, and the biology of aging.