9UGA

SARM1 senses DNA to promote NAD degradation

Summary for 9UGA

• Entry DOI: 10.2210/pdb9uga/pdb
• EMDB information: 64134
• Descriptor: NAD(+) hydrolase SARM1 (1 entity in total)
• Functional Keywords: dna binding protein, octamer, hydrolase
• Biological source: Homo sapiens (human)
• Total number of polymer chains: 8
• Total formula weight: 611771.75

Authors

Wang, L.N.,Yang, Q.K. (deposition date: 2025-04-11, release date: 2025-11-05, Last modification date: 2025-12-24)

Primary citation

Wang, L.,Liu, Q.,Li, S.,Wang, N.,Chen, Y.,Chen, J.,Wang, L.,Huang, Y.,Sun, Z.,Dong, L.,Li, S.,Liu, Q.,Gao, S.,Ma, X.,Song, C.,Yang, Q.
SARM1 senses dsDNA to promote NAD + degradation and cell death.
Cell, 188:7137-7154.e21, 2025

PubMed Abstract: 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.

PubMed: 41138726
DOI: 10.1016/j.cell.2025.09.026

Experimental method

ELECTRON MICROSCOPY (3.06 Å)