A20/TNFAIP3 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA-Damaging Therapy

• Published in: Cancer research (Chicago, Ill.) Vol. 78; no. 4; pp. 1069 - 1082
• Main Authors: Yang, Chuanzhen, Zang, Weicheng, Tang, Zefang, Ji, Yapeng, Xu, Ruidan, Yang, Yongfeng, Luo, Aiping, Hu, Bin, Zhang, Zemin, Liu, Zhihua, Zheng, Xiaofeng
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research, Inc 15.02.2018
• Subjects: Breast cancer; Breast carcinoma; Cancer; Chemotherapy; Clonal deletion; Damage prevention; Deoxyribonucleic acid; Dismantling; DNA; DNA damage; DNA repair; Editing; Enzymatic activity; Enzymes; Error detection; Genomes; Histone H2A; Homologous recombination; Homology; Inflammation; Interfaces; Invasiveness; NF-κB protein; Radiation therapy; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.can-17-2143

A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen, DDR can blunt the efficacy of chemotherapy and radiotherapy that cause lethal DNA breakage in cancer cells. Thus, blocking DDR may improve the efficacy of these modalities. Here, we report a new DDR mechanism that interfaces with inflammatory signaling and might be blocked to improve anticancer outcomes. Specifically, we report that the ubiquitin-editing enzyme A20/TNFAIP3 binds and inhibits the E3 ubiquitin ligase RNF168, which is responsible for regulating histone H2A turnover critical for proper DNA repair. A20 induced after DNA damage disrupted RNF168-H2A interaction in a manner independent of its enzymatic activity. Furthermore, it inhibited accumulation of RNF168 and downstream repair protein 53BP1 during DNA repair. A20 was also required for disassembly of RNF168 and 53BP1 from damage sites after repair. Conversely, A20 deletion increased the efficiency of error-prone nonhomologous DNA end-joining and decreased error-free DNA homologous recombination, destablizing the genome and increasing sensitivity to DNA damage. In clinical specimens of invasive breast carcinoma, A20 was widely overexpressed, consistent with its candidacy as a therapeutic target. Taken together, our findings suggest that A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NFκB-regulated ubiquitin-editing enzyme and the DDR pathway. This study identifies the ubiquitin-editing enzyme A20 as a key factor in mediating cancer cell resistance to DNA-damaging therapy, with implications for blocking its function to leverage the efficacy of chemotherapy and radiotherapy. .