Nuclear Transglutaminase 2 interacts with topoisomerase II⍺ to promote DNA damage repair in lung cancer cells

Journal of Experimental & Clinical Cancer Research

Hongran Qin¹  Yuanyuan Chen²  Fu Gao²  Yanyong Yang²  Hui Shen²  Zhe Liu²  Kun Cao²  Xiao Lei³  Jianming Cai⁴ 

[1] Department of Nuclear Radiation, Shanghai Pulmonary Hospital, Tongji University, 507, Zhengmin Road, 200433, Shanghai, P.R. China;Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, 800, Xiangyin Road, 200433, Shanghai, P.R. China;Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, 800, Xiangyin Road, 200433, Shanghai, P.R. China;Department of Radiation Oncology, The First Medical Center of PLA General Hospital, Beijing, P.R. China;Department of Radiation Medicine, Faculty of Naval Medicine, Naval Medical University, 800, Xiangyin Road, 200433, Shanghai, P.R. China;School of Public Health and Management, Wenzhou Medical University, University Town, Wenzhou, Zhejiang, P.R. China;

关键词: DNA damage repair;    Transglutaminase 2 (TG2);    DNA double strand breaks (DSBs);    Topoisomerase IIα (TOPOIIα);    Cancer therapy;   

DOI  :  10.1186/s13046-021-02009-2

来源: Springer

【 摘 要 】

BackgroundTo block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. DSB repair depends on a sequential activation of DNA repair factors that may be potentially targeted for clinical cancer therapy. Up to now, many protein components of DSB repair complex remain unclear or poorly characterized. In this study, we discovered that Transglutaminase 2 (TG2) acted as a new component of DSB repair complex.MethodsA bioinformatic analysis was performed to identify DNA damage relative genes from dataset from The Cancer Genome Atlas. Immunofluorescence and confocal microscopy were used to monitor the protein localization and recruitment kinetics. Furthermore, immunoprecipitation and mass spectrometry analysis were performed to determine protein interaction of both full-length and fragments or mutants in distinct domain. In situ lung cancer model was used to study the effects cancer therapy in vivo.ResultsAfter DSB induction, cytoplasmic TG2 was extensively mobilized and translocated into nucleus after phosphorylated at T162 site by DNA-PKcs. Nuclear TG2 quickly accumulated at DSB sites and directly interacting with Topoisomerase IIα (TOPOIIα) with its TGase domain to promote DSB repair. TG2 deficient cells lost capacity of DSB repair and become susceptible to ionizing radiation. Specific inhibition of TG2-TOPOIIα interaction by glucosamine also significantly inhibited DSB repair, which increased sensitivity in lung cancer cells and engrafted lung cancers.ConclusionsThese findings elucidate new mechanism of TG2 in DSB repair trough directly interacting with TOPOIIα, inhibition of which provided potential target for overcoming cancer resistance.

【 授权许可】

CC BY