Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
Department of Breast Oncology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China.
EMBO Rep. 2019 May;20(5). doi: 10.15252/embr.201846166. Epub 2019 Apr 2.
The bromodomain-containing protein 7 (BRD7) is a tumour suppressor protein with critical roles in cell cycle transition and transcriptional regulation. Whether BRD7 is regulated by post-translational modifications remains poorly understood. Here, we find that chemotherapy-induced DNA damage leads to the rapid degradation of BRD7 in various cancer cell lines. PARP-1 binds and poly(ADP)ribosylates BRD7, which enhances its ubiquitination and degradation through the PAR-binding E3 ubiquitin ligase RNF146. Moreover, the PARP1 inhibitor Olaparib significantly enhances the sensitivity of BRD7-positive cancer cells to chemotherapeutic drugs, while it has little effect on cells with low BRD7 expression. Taken together, our findings show that PARP1 induces the degradation of BRD7 resulting in cancer cell resistance to DNA-damaging agents. BRD7 might thus serve as potential biomarker in clinical trial for the prediction of synergistic effects between chemotherapeutic drugs and PARP inhibitors.
溴结构域蛋白 7（BRD7）是一种肿瘤抑制蛋白，在细胞周期转换和转录调控中具有关键作用。BRD7 是否受翻译后修饰调控仍知之甚少。在这里，我们发现化疗诱导的 DNA 损伤导致各种癌细胞系中 BRD7 的快速降解。PARP-1 结合并多聚（ADP-核糖基）化 BRD7，通过 PAR 结合 E3 泛素连接酶 RNF146 增强其泛素化和降解。此外，PARP1 抑制剂奥拉帕尼显著增强了 BRD7 阳性癌细胞对化疗药物的敏感性，而对 BRD7 低表达的细胞影响很小。总之，我们的研究结果表明，PARP1 诱导 BRD7 的降解，导致癌细胞对 DNA 损伤剂产生耐药性。因此，BRD7 可能作为临床实验中预测化疗药物和 PARP 抑制剂协同作用的潜在生物标志物。
