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Peer-reviewedCC BYAdvanced science (Weinheim, Baden-Wurttemberg, Germany)

DTX3 Suppresses the NPM3-RUVBL1 Axis to Inhibit Homologous Recombination Repair and Abrogate Tumor Radioresistance.

  • Jia-Hao Xiao1
  • Chang-Jun Xie1
  • Yan-Hua Chen1
  • Hao Cheng1
  • Shuang-Hui Li1
  • Wei Li2
  • Ya-Wen Bin2
  • Rui-Min He1
  • Ying-Qing Li3
  • Ping Feng1
  1. 1Department of Cancer Center, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, China.
  2. 2Department of Breast and Thyroid Surgery, Hengyang Medical School, The Second Affiliated Hospital, University of South China, Hengyang, Hunan, China.
  3. 3State Key Laboratory of Oncology in South China, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University Cancer Center, Guangzhou, China.
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Abstract

Aberrant remodeling of DNA damage repair pathways after radiotherapy constitutes a primary driver of tumor radioresistance and compromised therapeutic efficacy. Ubiquitination has been reported as a critical post-translational modification governing the DNA damage response and repair cascade. However, the precise molecular mechanisms underlying ubiquitination-mediated radioresistance remain poorly characterized. The E3 ubiquitin ligase Deltex 3 (DTX3) is validated as a negative regulator of tumor radioresistance that improves radiotherapy efficacy in vitro and in vivo models. Mechanistically, DTX3 physically interacts with nucleophosmin 3 (NPM3), catalyzes K27-linked polyubiquitination of NPM3 at the Lys102 residue, and consequently triggers proteasomal degradation of NPM3. Loss of NPM3 further destabilizes the RUVBL1-TIP60 complex, diminishes H4K16 acetylation, and impairs homologous recombination repair. Consistently, elevated NPM3 expression counteracts DTX3-mediated radiosensitization. Clinically, low DTX3 levels are correlated with inferior overall survival and elevated post-radiotherapy recurrence across multiple human malignancies. The study reveals DTX3 as a potent suppressor of homologous recombination repair and a promising therapeutic candidate to overcome tumor radioresistance.

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Cite

BibTeXRIS
BibTeX
@article{xiao2026dtx3,
  title = {{DTX3 Suppresses the NPM3-RUVBL1 Axis to Inhibit Homologous Recombination Repair and Abrogate Tumor Radioresistance.}},
  author = {Jia-Hao Xiao and Chang-Jun Xie and Yan-Hua Chen and Hao Cheng and Shuang-Hui Li and Wei Li and Ya-Wen Bin and Rui-Min He and Ying-Qing Li and Ping Feng},
  journal = {Advanced science (Weinheim, Baden-Wurttemberg, Germany)},
  year = {2026},
  month = oct,
  doi = {10.1002/advs.78573},
  url = {https://europepmc.org/article/MED/42958702},
  note = {CC BY},
}
RIS
TY  - JOUR
TI  - DTX3 Suppresses the NPM3-RUVBL1 Axis to Inhibit Homologous Recombination Repair and Abrogate Tumor Radioresistance.
AU  - Jia-Hao Xiao
AU  - Chang-Jun Xie
AU  - Yan-Hua Chen
AU  - Hao Cheng
AU  - Shuang-Hui Li
AU  - Wei Li
AU  - Ya-Wen Bin
AU  - Rui-Min He
AU  - Ying-Qing Li
AU  - Ping Feng
PY  - 2026
DA  - 2026/10/29
JO  - Advanced science (Weinheim, Baden-Wurttemberg, Germany)
DO  - 10.1002/advs.78573
UR  - https://europepmc.org/article/MED/42958702
AB  - Aberrant remodeling of DNA damage repair pathways after radiotherapy constitutes a primary driver of tumor radioresistance and compromised therapeutic efficacy. Ubiquitination has been reported as a critical post-translational modification governing the DNA damage response and repair cascade. However, the precise molecular mechanisms underlying ubiquitination-mediated radioresistance remain poorly characterized. The E3 ubiquitin ligase Deltex 3 (DTX3) is validated as a negative regulator of tumor radioresistance that improves radiotherapy efficacy in vitro and in vivo models. Mechanistically, DTX3 physically interacts with nucleophosmin 3 (NPM3), catalyzes K27-linked polyubiquitination of NPM3 at the Lys102 residue, and consequently triggers proteasomal degradation of NPM3. Loss of NPM3 further destabilizes the RUVBL1-TIP60 complex, diminishes H4K16 acetylation, and impairs homologous recombination repair. Consistently, elevated NPM3 expression counteracts DTX3-mediated radiosensitization. Clinically, low DTX3 levels are correlated with inferior overall survival and elevated post-radiotherapy recurrence across multiple human malignancies. The study reveals DTX3 as a potent suppressor of homologous recombination repair and a promising therapeutic candidate to overcome tumor radioresistance.
SN  - 2198-3844
ER  -