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

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.