Bioengineering a Luminous Biosensor for Aberrant DNA Detection

Cells contain a DNA sensor called cGAS, which alerts the immune system to viral and bacterial infections, cell death, and cancer-related transformations. A research team led by Ikerbasque Research Professor Sergio P. Acebrón (University of the Basque Country and Heidelberg University) bioengineered this fundamental cellular mechanism into a novel fluorescent biosensor.

This innovative tool, detailed in the EMBO Journal, enables the visualization of the innate immune response to abnormal DNA across cell populations, offering a versatile resource for biomedical research.

The mitochondria (mitochondrial DNA) and nucleus (genomic DNA) are where each of the cells stores its genetic material. DNA outside of these compartments can be detected by a conserved molecular pathway regulated by the proteins cGAS, STING, and IRF3. Secondary messengers, such as cGAMP and Interferon, can then relay this information to the immune system and neighboring cells.

Therefore, this mechanism acts as a Swiss knife against foreign DNA from bacterial and viral infections as well as against cellular transformation and death, which frequently results in host DNA by-products outside of the nucleus and/or mitochondria.

It is interesting to note that immune evasion caused by viruses and cancer is based on down regulation of these mechanisms, whereas auto-immune illnesses are linked to their aberrant overexpression.  However, studies on the topic have been hampered by the lack of biological reporters to visualize these cellular processes.

A Key Cellular “Detector”

This study demonstrates how the spatiotemporal and heterogeneous dynamics of the response to the intracellular and extracellular messenger cGAMP can be captured by tailoring the functional interplay of activated STING and IRF3.

The visualization of single cell and population responses to Herpes virus infection, mitochondrial DNA release during death, and other sources of aberrant DNA are made possible by this innovative fluorescent biosensor in conjunction with imaging-analysis tools.

Errors in the segregation of chromosomes containing genomic DNA, which may wind up outside the nucleus, are frequently linked to the formation of tumors. Since histones naturally pack the genomic DNA, the study demonstrates that missegregated chromosomes do not trigger the innate immune response through STING. This is significant since several treatment trials aimed to target chromosomally unstable tumors with STING.

A Breakthrough for the Scientific Community

By giving the community a way to visualize the innate immune response in intricate biological models, this study marks a substantial leap in the field's understanding. The Ikerbasque Foundation, Boehringer Ingelheim Fonds, and Heidelberg University's excellence program provided funding for the study.