Glutamine Synthetase Promotes Radiation Resistance via Facilitating Nucleotide Metabolism and Subsequent DNA Damage Repair

Radiation resistance is a critical problem in radiotherapy for cancer. Radiation kills tumor cells mainly through causing DNA damage. Thus, efficiency of DNA damage repair is one of the most important factors that limits radiotherapy efficacy. Glutamine physiologically functions to generate protein and nucleotides. Here, we study the impact of glutamine metabolism on cancer therapeutic responses, in particular under irradiation-induced stress. We show that radiation-resistant cells possessed low glycolysis, mitochondrial respiration, and TCA cycle but high glutamine anabolism. Transcriptome analyses revealed that glutamine synthetase (GS), an enzyme catalyzing glutamate and ammonia to glutamine, was responsible for the metabolic alteration. ChIP and luciferase reporter assays revealed that GS could be transcriptionally regulated by STAT5. Knockdown of GS delayed DNA repair, weakened nucleotide metabolism, and enhanced radiosensitivity both in vitro and in vivo. Our data show that GS links glutamine metabolism to radiotherapy response through fueling nucleotide synthesis and accelerating DNA repair. [Display omitted] •Radioresistant cancer cells reprogram metabolic flux toward glutamine anabolism•GS promotes cellular nucleotide synthesis for efficient DNA repair•High expression of GS facilitates growth of cancer cells under radiation stress•GS is transcriptionally regulated by STAT5 Radiation resistance is one of the limiting factors for therapeutic efficacy and results in cancer recurrence. Fu et al. identify GS as a switch that drives cellular metabolic flux toward nucleotide synthesis for efficient DNA repair and thus leads to radiation resistance of cancer cells.