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TitleSARM1 senses dsDNA to promote NAD degradation and cell death.
Journal, issue, pagesCell, Vol. 188, Issue 25, Page 7137-7154.e21, Year 2025
Publish dateDec 11, 2025
AuthorsLina Wang / Qiaoling Liu / Siru Li / Na Wang / Yan Chen / Junren Chen / Li Wang / Yuelin Huang / Zhen Sun / Ling Dong / Shao Li / Quentin Liu / Song Gao / Xiaochi Ma / Chengli Song / Qingkai Yang /
PubMed AbstractDetection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is ...Detection of DNA is a fundamental strategy for life to recognize non-self or abnormal-self to subsequently trigger the downstream responses. However, the mechanism underlying DNA sensing is incompletely understood. Here, we show that a key neural executioner, sterile alpha and Toll/interleukin-1 receptor (TIR) motif containing 1 (SARM1), senses double-stranded DNA (dsDNA) to promote cell death. dsDNA-bound and -activated SARM1 to degrade nicotinamide adenine dinucleotide (NAD) in a sequence-independent manner. SARM1 bound dsDNA via the TIR domain, and lysine residues in the TIR domain contributed to dsDNA binding. In the cellular context, cytosolic dsDNA from dsDNA transfection or chemotherapy treatment was colocalized with SARM1 and activated SARM1 to elicit NAD degradation and cell death, which was abrogated by SARM1 knockout or DNA-binding residue mutation. Consistently, SARM1 knockout blocked chemotherapy-induced neuropathy (CIN) in mice. Our results reveal SARM1 as a DNA sensor, which might be targetable for therapeutic interventions.
External linksCell / PubMed:41138726
MethodsEM (single particle)
Resolution3.06 Å
Structure data

64134

9uga

EMDB-64134, PDB-9uga:
SARM1 senses DNA to promote NAD degradation
Method: EM (single particle) / Resolution: 3.06 Å

Source
  • homo sapiens (human)
KeywordsHYDROLASE / DNA BINDING PROTEIN / OCTAMER

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