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

Cell Rep

Center for Molecular Medicine, Xiangya Hospital, Central South University, Changsha 410008, China; Key Laboratory of Molecular Radiation Oncology Hunan Province, Changsha 410008, China; Hunan International Science and Technology Collaboration Base of Precision Medicine for Cancer, Changsha 410008, China; National Clinical Research Center for Gerontology, Changsha 410008, China. Electronic address:

Published: July 2019

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.

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Source
http://dx.doi.org/10.1016/j.celrep.2019.07.002DOI Listing

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