Nuclear Transglutaminase 2 interacts with topoisomerase II\u237a to promote DNA damage repair in lung cancer cells

Xiao Lei,Yanyong Yang,Hui Shen,Hongran Qin,Kun Cao,Fu Gao,Yuanyuan Chen,Zhe Liu,Jianming Cai

doi:10.1186/s13046-021-02009-2

Abstract

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.

Highlights

To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death
Activities of Transglutaminase 2 (TG2) dynamically correlated with various activities of DNA damage repair DNA damage repair acted in many types of tumor cells to mainly resist to both radiotherapy and chemotherapy[5]
TGM2 expression was negatively correlated to both OS and progression-free survival (PFS) in the radiotherapy treated cancer patients (Fig. 1B, C), as well as the overall survival of all patients (Fig. S1B, C)

Summary

Introduction

To block repairs of DNA damages, especially the DNA double strand break (DSB) repair, can be used to induce cancer cell death. Many protein components of DSB repair complex remain unclear or poorly characterized. Deficiencies in functions of DNA damage repair result in accumulation of genetic mutations, leading to cell senescence, carcinogenesis or cell death [3, 4]. To completely elucidate the mechanisms of DNA damage repair is helpful of improving our realizations on the precise cellular response to multiple DNA damages, which can be applied to overcome the relative resistances of cancer cells during various clinical cancer therapies[7]. When DSB occurs, protein factors accumulate at sites of DSB to compose an activating DNA repair complex[10]. Many members of these factors are either still unknown or poorly characterized, which becomes a difficulty for intentionally controlling the process of DSB repair during clinical applications

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Discussion

Conclusion