Authors
Jia-Hao Xiao, Chang-Jun Xie, Yan-Hua Chen, Hao Cheng, Shuang-Hui Li, Wei Li, Ya-Wen Bin, Rui-Min He, Ying-Qing Li, Ping Feng
Published in
Advanced science (Weinheim, Baden-Wurttemberg, Germany). Oct 29, 2026. Epub Oct 29, 2026.
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.
PMID:
42958702
Bibliographic data and abstract were imported from PubMed on 30 Oct 2026.
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