The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region
The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region
复制标题
DOI：
10.1101/gad.2009411
复制
发表时间：
2011-03-01
影响因子：
10.5
通讯作者：
Reed, Robin
中科院分区：
文献类型：
--
作者：
Folco, Eric G.;Coil, Kaitlyn E.;Reed, Robin
U2 snRNA的分支点结合区（BBR）和内含子中的分支点序列（BPS）之间的双链体形成对于剪接是必需的。BBR和BPS都与U2小核核糖核蛋白（snRNP）相关的SF3b复合物相互作用，该复合物是抗肿瘤药物E7107的靶点。我们发现E7107通过阻止U2 snRNP与前体mRNA的紧密结合来阻断剪接体组装。E7107对U2 snRNP完整性无明显影响。相反，E7107消除了暴露BBR的U2 snRNP中的ATP依赖性构象变化。我们得出结论，SF3b是需要这种重塑，这暴露了BBR紧密U2 snRNP结合前mRNA。
Duplex formation between the branch point-binding region (BBR) of U2 snRNA and the branch point sequence (BPS) in the intron is essential for splicing. Both the BBR and BPS interact with the U2 small nuclear ribonucleoprotein (snRNP)-associated SF3b complex, which is the target of the anti-tumor drug E7107. We show that E7107 blocks spliceosome assembly by preventing tight binding of U2 snRNP to pre-mRNA. E7107 has no apparent effect on U2 snRNP integrity. Instead, E7107 abolishes an ATP-dependent conformational change in U2 snRNP that exposes the BBR. We conclude that SF3b is required for this remodeling, which exposes the BBR for tight U2 snRNP binding to pre-mRNA.