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

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.