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

Cell Reports
Shujun FuLun-Quan Sun

Abstract

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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Citations

May 29, 2020·The British Journal of Radiology·Martin Kery, Ioanna Papandreou
Jul 30, 2020·Cancers·Amandine Moretton, Joanna I Loizou
Sep 19, 2020·Experimental & Molecular Medicine·Hee Chan YooJung Min Han
Jul 13, 2020·Cellular and Molecular Life Sciences : CMLS·Fang WeiZhaoyang Zeng
Aug 1, 2020·Nature Communications·Weihua ZhouDaniel R Wahl
Jan 16, 2021·Journal of Zhejiang University. Science. B·Yihan Peng, Huadong Pei
Feb 12, 2021·International Journal of Molecular Sciences·Go Woon KimSo Hee Kwon
Mar 7, 2021·Cancers·Oleg ShuvalovNickolai Barlev
Mar 24, 2021·Signal Transduction and Targeted Therapy·Zeyu WangQuan Cheng
Apr 4, 2021·Cancers·Anaís Sánchez-CastilloKim R Kampen
Apr 10, 2021·Frontiers in Cell and Developmental Biology·Thais SobanskiEmma Bolderson
Apr 16, 2021·Frontiers in Oncology·Funmilayo O AdeshakinXiaochun Wan
Oct 11, 2021·The Plant Journal : for Cell and Molecular Biology·Raju MondalSanjib Kumar Chattopadhyay
Sep 29, 2021·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Yuan FangDehua Wu

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