Proper regulation of gene-expression relies on specific protein–protein interactions between a myriad of epigenetic regulators. As such, mutation of genes encoding epigenetic regulators often drive cancer and developmental disorders. Additional sex combs-like protein 1 (ASXL1) is a key example, where mutations frequently drive haematological cancers and can cause developmental disorders. It has been reported that nonsense mutations in ASXL1 promote an interaction with BRD4, another central epigenetic regulator. Here we provide a molecular mechanism for the BRD4-ASXL1 interaction, demonstrating that a motif near to common truncation breakpoints of ASXL1 contains an epitope that binds the ET domain within BRD4. Binding-studies show that this interaction is analogous to common ET-binding modes of BRD4-interactors, and that all three ASX-like protein orthologs (ASXL1–3) contain a functional ET domain-binding epitope. Crucially, we observe that BRD4-ASXL1 binding is markedly increased in the prevalent ASXL1^Y591X truncation that maintains the BRD4-binding epitope, relative to full-length ASXL1 or truncated proteins that delete the epitope. Together, these results show that ASXL1 truncation enhances BRD4 recruitment to transcriptional complexes via its ET domain, which could misdirect regulatory activity of either BRD4 or ASXL1 and may inform potential therapeutic interventions.

基因表达的正确调控依赖于无数表观遗传调控因子之间特定的蛋白质-蛋白质相互作用。因此，编码表观遗传调节因子的基因突变通常会导致癌症和发育障碍。额外的性梳状蛋白 1 (ASXL1) 是一个关键的例子，其中的突变经常导致血液癌症并可能导致发育障碍。据报道，ASXL1 中的无义突变促进了与另一个中央表观遗传调节因子 BRD4 的相互作用。在这里，我们提供了 BRD4-ASXL1 相互作用的分子机制，证明靠近 ASXL1 常见截断断点的基序包含结合 BRD4 内 ET 域的表位。结合研究表明，这种相互作用类似于 BRD4 相互作用子的常见 ET 结合模式，并且所有三个 ASX 样蛋白直向同源物 (ASXL1-3) 都包含一个功能性 ET 结构域结合表位。至关重要的是，我们观察到 BRD4-ASXL1 结合在普遍的 ASXL1 中显着增加^Y591X截断保留 BRD4 结合表位，相对于全长 ASXL1 或删除表位的截断蛋白。总之，这些结果表明，ASXL1 截断通过其 ET 域增强了 BRD4 向转录复合物的募集，这可能会误导 BRD4 或 ASXL1 的调节活动，并可能为潜在的治疗干预提供信息。