抗肿瘤药物 E7107 揭示了 SF3b 在重塑 U2 snRNP 以暴露分支点结合区域方面的重要作用。
The anti-tumor drug E7107 reveals an essential role for SF3b in remodeling U2 snRNP to expose the branch point-binding region.
机构信息
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
出版信息
Genes Dev. 2011 Mar 1;25(5):440-4. doi: 10.1101/gad.2009411.
Abstract
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.
摘要
U2 snRNA 的分支点结合区（BBR）与内含子中的分支点序列（BPS）之间的双链形成对于剪接至关重要。BBR 和 BPS 均与 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 的靶标。我们表明，E7107 通过阻止 U2 snRNP 与前体 mRNA 的紧密结合来阻止剪接体组装。E7107 对 U2 snRNP 的完整性没有明显影响。相反，E7107 消除了 U2 snRNP 中依赖 ATP 的构象变化，从而暴露了 BBR。我们得出的结论是，SF3b 是这种重塑所必需的，它暴露了 BBR，以便 U2 snRNP 与前体 mRNA 紧密结合。
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