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

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A20 Regulates the DNA Damage Response and Mediates Tumor Cell Resistance to DNA Damaging Therapy Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. A20 regulates the DNA damage response and mediates tumor cell resistance to DNA damaging therapy Chuanzhen Yang1,2, Weicheng Zang1,2, Zefang Tang3, Yapeng Ji1,2, Ruidan Xu1,2, Yongfeng Yang1,2, Aiping Luo4, Bin Hu1,2, Zemin Zhang3, Zhihua Liu4, and Xiaofeng Zheng1,2 1State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking University, Beijing, China. 2Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing, China. 3Biodynamic Optical Imaging Center, School of Life Sciences, Peking University, Beijing, China. 4State Key Laboratory of Molecular Oncology, Cancer Institute and Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China. Running Title A20 regulates the DNA damage response Corresponding Author: Xiaofeng Zheng, Department of Biochemistry and Molecular Biology, School of Life Sciences, Peking University, Beijing 100871, China. Phone: +86 10 62755712; E-mail: [email protected]. Disclosure of Potential Conflicts of Interest No potential conflicts of interest were disclosed. 1 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Abstract A competent DNA damage response (DDR) helps prevent cancer, but once cancer has arisen DDR can blunt the efficacy of chemotherapy and radiotherapy which 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 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. Further, 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 non-homologous 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 A20 is critical for proper functioning of the DDR in cancer cells and it establishes a new link between this NF-κB regulated ubiquitin-editing enzyme and the DDR pathway. 2 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Mammalian cells are exposed to various physical and chemical agents that induce DNA damage. A single cell is likely to encounter tens of thousands of DNA lesions per day (1, 2). DNA double strand breaks (DSBs) are among the most dangerous types of DNA damage, and unrepaired or incorrectly repaired DSBs lead to genome instability, cancer and aging (3, 4). To maintain genomic integrity, cells have evolved a set of complex signaling cascades known as the DNA damage response (DDR) (5). In response to DSBs, checkpoint kinase ATM (Ataxia Telangiectasia Mutated) phosphorylates H2AX (also designated as γH2AX) near the damage sites, leading to recruitment and phosphorylation of MDC1 (6, 7). In addition to kinase signaling, ubiquitination also plays an important role in the DDR. E3 ligase RNF8 is recruited by phosphorylated MDC1 and ubiquitinates histone H1 (8). Next, another E3 ligase, RNF168, is recruited to catalyze monoubiquitination of H2A and H2AX at Lys13 and Lys15, which initiates the subsequent formation of a lysine 63-linked polyubiquitin chain. The ubiquitin signaling catalyzed by the RNF8/RNF168 cascade promotes recruitment of downstream repair proteins such as 53BP1 (9, 10). Error-free homologous recombination (HR) and error-prone non-homologous end-joining (NHEJ) are the major pathways to repair DSBs (1, 3). 53BP1 is a crucial effector that promotes DSB repair through NHEJ (3, 11). NHEJ is important for maintaining genome stability; however, over-use of NHEJ for repair leads to chromosomal translocation and genome instability (12, 13). Therefore, a proper cellular response to DNA damage is crucial for the maintenance of normal cell function. For instance, defective DNA repair results in a human immunodeficiency disorder called RIDDLE (radio sensitivity, immunodeficiency dysmorphic features and learning difficulties) syndrome and enhanced DNA repair capacity renders cancer cells resistant to radiotherapy and chemotherapy (14, 15). This connection reveals the importance of delicate regulation of the DDR at DSBs. 3 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. In addition to E3 ligases, deubiquitinating enzymes (DUBs) also participate in the DDR pathway through regulating H2A ubiquitination. The human genome encodes approximately 90 DUBs, which are divided into five families: UCH (ubiquitin C-terminal hydrolases), USP (ubiquitin specific proteases), OTU (ovarian tumor proteases), Josephin and JAMM (JAB1/MPN/Mov34 metalloenzyme). So far, most of the identified DUBs that antagonize DSB-induced H2A ubiquitination belong to the USP family. USP3 and USP44 abolish accumulation of RNF168 and 53BP1 at DNA damage sites (16, 17). Recently, USP51 was demonstrated to specifically deubiquitinate H2A at Lys13 and Lys15 and fine-tune the DDR (18). USP16 deubiquitinates H2A at Lys 119 and represses gene transcription (19). OTUB1 is the only reported deubiquitinating enzyme in the OTU family that inhibits RNF168- mediated H2A ubiquitination. Independent of its DUB catalytic activity, OTUB1 antagonizes H2A ubiquitination via direct binding to and inhibition of E2 UBC13 (20). Although recent studies have revealed the importance of deubiquitinating enzymes in tightly controlling histone ubiquitination during the DDR, it remains unclear whether other DUBs from the OTU family can regulate DSB-induced H2A ubiquitination and the DDR. TNFAIP3/A20, a member of the OTU deubiquitinase family, is a primary protein expressed in human venous endothelial cells in response to TNF, IL-1, and LPS. Recent studies reveal that A20 is also expressed in other cell types in response to stimuli such as H2O2 and TPA (21). The most well-studied function of A20 is negative regulation of inflammation and immunity (22). In mice, knocking out A20 results in severe inflammation and cachexia, followed by death two weeks after birth (23). Moreover, several studies have identified somatic mutations, deletion and aberrant expression of the TNFAIP3/A20 gene in various kinds of tumors (24-26). These studies reveal the importance of fully exploring the functions of A20 and its connection with tumors. 4 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Here, we identify A20/TNFAIP3 as a negative regulator of RNF168-mediated ubiquitination of H2A Lys13,15 (H2AK13,15ub). We find that NF-κB is activated in response to DNA damage and binds to the A20 promoter, leading to up-regulation of A20 expression. Subsequently, more A20 binds to chromatin and regulates the DDR. Deletion of A20 increases the persistence of RNF168 and 53BP1 foci at DNA damage sites and genome instability. Importantly, A20 is often up-regulated in invasive breast carcinomas, and knockout of A20 increases the sensitivity of cancer cells to radiotherapy and chemotherapy, suggesting that A20 is a potential target for cancer therapy. 5 Downloaded from cancerres.aacrjournals.org on October 2, 2021. © 2017 American Association for Cancer Research. Author Manuscript Published OnlineFirst on December 12, 2017; DOI: 10.1158/0008-5472.CAN-17-2143 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and Methods Antibodies, reagents and plasmids The antibodies and reagents used in this study were listed in the Supplementary Method. OTUD3, OTUD5, and OTUD6B cDNAs were kindly provided by Dr. Lingqiang Zhang at the Beijing Institute of Radiation Medicine. Human wild-type TNFAIP3 (A20) and mutants, H2A-K118,119R mutant, RNF168 and deletion mutants, TAX1BP1, ITCH and RNF11 were inserted into the 3Flag-pcDNA vector. A20, RNF8 and RNF168 were inserted into the 3Myc- pcDNA vector. A20-1-370 (A20-N) and
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