Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains
Interactome Rewiring Following Pharmacological Targeting of BET Bromodomains
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DOI：
10.1016/j.molcel.2018.11.006
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发表时间：
2019-02-07
期刊：
影响因子：
16
通讯作者：
Gingras, Anne-Claude
中科院分区：
文献类型：
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作者：
Lambert, Jean-Philippe;Picaud, Sarah;Gingras, Anne-Claude
靶向溴末端 (BET) 家族的溴结构域 (BRD) 为癌症和其他疾病的治疗干预提供了机会。在这里，我们分析了用泛 BET BRD 抑制剂 JQ1 治疗后 BRD2、BRD3、BRD4 和 BRDT 的相互作用组，揭示了相互作用景观的广泛重新布线，确定了 603 个独特相互作用因子的三种不同行为类别。一组蛋白质通过规范和新的结合模式以 JQ1 敏感的方式与 BET BRD 结合，而两类额外末端 (ET) 结构域结合基序介导不依赖于乙酰化的相互作用。最后，我们发现 JQ1 处理后几种相互作用意外增加，这些相互作用定义了 BRD3 在调节 rRNA 合成和潜在的 RNAPII 依赖性基因表达中的负功能，从而导致细胞增殖减少。总之，我们的数据强调了 BET 蛋白模块对其相互作用组的贡献，从而可以更好地理解响应 JQ1 的药理学重连。
Targeting bromodomains (BRDs) of the bromo-andextra-terminal (BET) family offers opportunities for therapeutic intervention in cancer and other diseases. Here, we profile the interactomes of BRD2, BRD3, BRD4, and BRDT following treatment with the pan-BET BRD inhibitor JQ1, revealing broad rewiring of the interaction landscape, with three distinct classes of behavior for the 603 unique interactors identified. A group of proteins associate in a JQ1-sensitive manner with BET BRDs through canonical and new binding modes, while two classes of extra-terminal (ET)-domain bindingmotifs mediate acetylation-independent interactions. Last, we identify an unexpected increase in several interactions following JQ1 treatment that define negative functions for BRD3 in the regulation of rRNA synthesis and potentially RNAPII-dependent gene expression that result in decreased cell proliferation. Together, our data highlight the contributions of BET protein modules to their interactomes allowing for a better understanding of pharmacological rewiring in response to JQ1.