TIGAR regulates DNA damage and repair through pentosephosphate pathway and Cdk5-ATM pathway.
Previous study revealed that the protective effect of TIGAR in cell survival is mediated through the increase in PPP (pentose phosphate pathway) flux. However, it remains unexplored if TIGAR plays an important role in DNA damage and repair. This study investigated the role of TIGAR in DNA damage response (DDR) induced by genotoxic drugs and hypoxia in tumor cells. Results showed that TIGAR was increased and relocated to the nucleus after epirubicin or hypoxia treatment in cancer cells. Knockdown of TIGAR exacerbated DNA damage and the effects were partly reversed by the supplementation of PPP products NADPH, ribose, or the ROS scavenger NAC. Further studies with pharmacological and genetic approaches revealed that TIGAR regulated the phosphorylation of ATM, a key protein in DDR, through Cdk5. The Cdk5-AMT signal pathway involved in regulation of DDR by TIGAR defines a new role of TIGAR in cancer cell survival and it suggests that TIGAR may be a therapeutic target for cancers.
Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Hong-Pei
HP
Yu
Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Jia-Ming
JM
Xie
Department of General Surgery, the First People's Hospital of Wu Jiang, Suzhou 215004, China.
Bin
B
Li
Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Yi-Hui
YH
Sun
Department of General Surgery, the First People's Hospital of Wu Jiang, Suzhou 215004, China.
Quan-Geng
QG
Gao
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University Suzhou 215123, China.
Zhi-Hui
ZH
Ding
Department of General Surgery, the Second Affiliated Hospital of Soochow University, Suzhou 215004, China.
Hao-Rong
HR
Wu
Department of Pharmacology and Laboratory of Aging and Nervous Diseases, Jiangsu Key Laboratory of Translational Research and Therapy for Neuro-Psycho-Diseases, College of Pharmaceutical Science, Soochow University Suzhou 215123, China.
Zheng-Hong
ZH
Qin
D051017:Apoptosis Regulatory Proteins; D064007:Ataxia Telangiectasia Mutated Proteins / Q000235:genetics*; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D051360:Cyclin-Dependent Kinase 5 / Q000235:genetics*; D004249:DNA Damage / Q000187:drug effects / Q000235:genetics*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics*; D015251:Epirubicin / Q000494:pharmacology; D056945:Hep G2 Cells; D006801:Humans; D000860:Hypoxia / Q000235:genetics / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics*; D009249:NADP / Q000235:genetics; D010427:Pentose Phosphate Pathway / Q000187:drug effects / Q000235:genetics*; D010744:Phosphoric Monoester Hydrolases; D010766:Phosphorylation / Q000187:drug effects / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics*
D051017:Apoptosis Regulatory Proteins; D047908:Intracellular Signaling Peptides and Proteins; D017382:Reactive Oxygen Species; D015251:Epirubicin; D009249:NADP; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051360:Cyclin-Dependent Kinase 5; C495905:CDK5 protein, human; D010744:Phosphoric Monoester Hydrolases; C512708:TIGAR protein, human