193: SARM1, DNA, and the Death Signal

️Episode 193: SARM1, DNA, and the Death Signal

In this episode of PaperCast Base by Base, we explore how the axon-degenerating enzyme SARM1 acts as a double-stranded DNA sensor that triggers NAD+ loss, cell death, and chemotherapy-induced neuropathy, opening up new possibilities for neuroprotective therapies.

Study Highlights:
The authors show that the immune adaptor SARM1 directly binds double-stranded DNA via its TIR domain and, once activated, rapidly degrades cellular NAD+ in a sequence-independent but length-dependent manner. Using a combination of biochemical assays and structural analyses, they demonstrate that SARM1 forms multimeric complexes with linear DNA, with optimal activation occurring when DNA fragments are long enough to engage multiple SARM1 molecules. In cells, cytosolic DNA introduced by transfection or released during chemotherapy colocalizes with SARM1, driving NAD+ depletion and promoting cell death, whereas mutations that disrupt DNA binding or complete knockout of SARM1 blunt this response. In mouse models, loss of SARM1 protects against chemotherapy-induced neuropathy, linking DNA sensing by SARM1 directly to treatment-related neurotoxicity and positioning this pathway as a therapeutic target.

Conclusion:
By revealing SARM1 as a double-stranded DNA sensor that couples cytosolic DNA to NAD+ degradation, cell death, and chemotherapy-induced neuropathy, this study highlights a druggable axis for preserving neural function during cancer treatment.

Reference:
Wang L, Liu Q, Li S, et al. SARM1 senses dsDNA to promote NAD+ degradation and cell death. Cell. 2025;188:1–18. https://doi.org/10.1016/j.cell.2025.09.026

License:
This episode is based on an open-access article published under the Creative Commons Attribution 4.0 International License (CC BY 4.0) – https://creativecommons.org/licenses/by/4.0/

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