SARM1 senses dsDNA to promote NAD+ degradation and cell death

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<sup>+</sup>) 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<sup>+</sup> 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.

Authors

Institutions

Publication Details

Journal
Cell
Published
2025-10-24
DOI
https://doi.org/10.1016/j.cell.2025.09.026
Citations
4
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
3.22
Controls
|||
ALL TIME
JAN
FEB
MAR
APR
MAY
JUN
JUL
AUG
SEP
OCT
article

SARM1 senses dsDNA to promote NAD+ degradation and cell death

J. Chen, Qingkai Yang, Ling Dong, Shao Li et al.
4 citations
Cell
RNA modifications and cancer
3.22
article

SARM1 senses dsDNA to promote NAD+ degradation and cell death

J. Chen, Qingkai Yang, Ling Dong, Shao Li, Siru Li, Quentin Liu, Li Wang, Lina Wang, Qiaoling Liu, Yan Chen, Yi Huang, Xiaochi Ma, Song Gao, Zhen Sun, Na Wang, Chengli Song
article en
4 citations

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<sup>+</sup>) 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<sup>+</sup> 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.

CellVol. 188(25)
Harbin Medical University (CN), Sun Yat-sen University (CN), Dalian Institute of Chemical Physics (CN), Dalian Medical University (CN), Chinese Academy of Sciences (CN), Second Affiliated Hospital of Dalian Medical University (CN), Third Affiliated Hospital of Harbin Medical University (CN), Sun Yat-sen University Cancer Center (CN), State Key Laboratory of Oncology in South China
Openalex Percentile: Top 7%
RNA modifications and cancer
3.22
DOIOpen Access PDFOpenAlex
AI Navigator

Ask Laika to Summarize, Analyze, and Connect papers live on the map.

Summarize Papers & Methodologies

Extract key findings, datasets, and comparative methods across publications.

Benchmark Rankings & Visual Analytics

Rank top research institutions, authors, funders, topics, and journals by Field-Weighted Citation Impact (FWCI) and paper volume with instant charts.

Connect Distant Disciplines

Bridge topological clusters on the map to find hidden collaborative intersections.