Brr2解旋U4/U6 SnRNAs的调控机制

前体mRNA(precursor messager RNA,pre-mRNA)剪接是去除内含子和将外显子彼此连接形成成熟mRNA的过程。剪接过程在一个呈动态变化的大核糖核蛋白(ribonucleoprotein, RNP)复合体,即剪接体催化作用下完成。DExD/H-box RNA解旋酶在剪接体组装、激活及解聚过程中都发挥着重要作用。Brr2(bad response to refrigeration 2)这种DExD/H-box RNA解旋酶是构成U5稳定的亚单位。Brr2含有两个串联解旋酶盒结构,在剪接体激活中负责U4/U6的解旋,还参与剪接体催化及解聚过程,因此Brr2在剪接过程中必需具备严格的调控机制。在剪接过程中,Prp8的C端包含两个连续的RNase H域和Jab1/MPN域,能够正负调控Brr2活性。Snu114在调节Brr2活性中具有非常重要的作用。此外,Brr2通过C端解旋酶盒(C-terminal cassette, CC)与N末端域(N-terminal region)进行分子内的自我活性调节。本文综述了近年来在Brr2的分子间和分子内活性调节机制的研究进展,这些不同的调节机制协同作用才确保真核生物pre-mRNA可变剪接的保真性。

Regulatory Mechanism of Brr2 for Unwinding U4/U6 SnRNAs

Pre-mRNA splicing is a process that involves removal of the introns and ligation of neighboring exons during mRNA maturation. The splicing reaction is catalyzed by the spliceosome, a huge dynamic ribonucleoprotein complex. DExD/H-box RNA helicases play important roles in spliceosomal assembly, activation, and disassembly process. The DExD/H-box RNA helicase, Brr2 (Bad response to refrigeration 2), is a stable subunit of U5 snRNP. Brr2 has a special structure, including two tandem helicase cassettes. Brr2 enzyme is responsible for U4/U6 unwinding during spliceosome activation and is implicated in the catalytic and disassembly phases of splicing, indicating that Brr2 requires tight regulation. The C-terminal of Prp8 protein, containing consecutive RNase H and Jab/MPN domains, can regulate Brr2 activity both positively and negatively. Snu114 can also modulate Brr2 activity. In addition, regulation of the helicase is achieved intramolecularly via the C-terminal cassette and the N-terminal region of Brr2. This review focuses on the recent findings in the inter- and intra- mechanisms of Brr2 activity regulation, which act in a coordinated manner, ensuring the fidelity in eukaryotic pre-mRNA alternative splicing.