mTORC1-Driven DDA1 Phosphorylation Promotes DNA Repair and Glioblastoma Progression

DDA1 is a protein involved in protein degradation, cell cycle regulation, and DNA damage repair. Interestingly, recent studies have revealed its differential expression across various tumor types. However, how DDA1 functions as a tumorogenic factor remains to be elucidated. Through studies in multiple glioblastoma cell models, we identified a physical association between cytoplasmic DDA1 and Raptor, a key component of lysosome-associated mTORC1. We report that amino acid stimulation triggers phosphorylation of DDA1 at serine 33, promoting its nuclear translocation and involvement in DNA damage repair. Integrated genomic and transcriptomic analyses revealed that the mTORC1-DDA1S33-DNA repair axis regulates the expression of a subset of metabolic genes, including ENO2, a glycolytic enzyme; CA12, which contributes to intracellular and extracellular pH homeostasis; and NMRK1, a key enzyme in nicotinamide riboside metabolism. Notably, DDA1 deficiency markedly impaired glioblastoma growth and triggered a compensatory upregulation of metabolic activity to sustain tumor cell survival. These metabolic genes likely supply essential nutrients required for effective DNA repair. Our findings establish DDA1 as a previously unrecognized phosphorylation target downstream of mTORC1, serving as a critical mediator of mTORC1-driven DNA damage response and a key regulator of glioblastoma progression, thereby expanding our understanding of gliomagenesis.