Phosphorylation of RBM39 by CDK13 stabilizes RAD50 mRNA to drive cisplatin resistance in endometrial cancer.

Platinum-resistant is a major therapeutic challenge in advanced endometrial cancer (EC), often driven by enhanced DNA damage repair, yet the underlying molecular mechanisms remain incompletely understood. Here, we report that cyclin-dependent kinase 13 (CDK13) is significantly overexpressed in EC tissues, where its high expression correlates with poor patient survival and clinical resistance to platinum-based chemotherapy. Functionally, CDK13 overexpression promoted EC cell proliferation and conferred cisplatin resistance both in vitro and in vivo, whereas its knockdown potentiated cisplatin-induced apoptosis and DNA damage. Mechanistically, through phosphoproteomic analysis, we identified the RNA-binding protein RNA-binding motif protein 39 (RBM39) as a critical downstream target of CDK13. We demonstrate that CDK13 directly phosphorylates RBM39 at serine 117, and this phosphorylation is essential for CDK13-mediated resistance. Crucially, phosphorylation at Ser117 enhanced the ability of RBM39 to bind and stabilize the mRNA of RAD50, a key DNA repair gene. Post-transcriptional regulation led to an increase in RAD50 protein, which facilitated the repair of DNA damage caused by cisplatin, promoting the survival of cells. The therapeutic relevance of this axis was confirmed in vivo, where dual knockdown of RBM39 and RAD50 synergistically sensitized EC xenografts to cisplatin. Our study first unveils a novel CDK13/RBM39/RAD50 signaling axis that drives platinum resistance in EC by enhancing DNA damage repair via mRNA stabilization, revealing promising therapeutic targets for overcoming chemoresistance in this malignancy.