Abstract
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.Significance: 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. Cancer Res; 78(4); 1069-82. ©2017 AACR.
Highlights
Mammalian cells are exposed to various physical and chemical agents that induce DNA damage
Histone H2A can be ubiquitinated at Lys118,119 or Lys13,15, and H2AK13,15ub induced by DNA damage triggers the recruitment of downstream repair proteins [10, 18]
This study reveals that chromatin-bound A20 plays an important role in connecting NFkB signaling and the DNA damage response (DDR)
Summary
Mammalian cells are exposed to various physical and chemical agents that induce DNA damage. 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. In addition to E3 ligases, deubiquitinating enzymes (DUB) participate in the DDR pathway through regulating H2A ubiquitination. 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. A20 is often upregulated 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
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