China-Japan Union Hospital of Jilin University, Jilin University, Changchun, Jilin 130033, China.
School of Life Sciences, Jilin University, Changchun, Jilin 130012, China.
J Biochem. 2022 Jul 25;172(2):117-126. doi: 10.1093/jb/mvac049.
While cancer-associated SF3B1 mutations causes alternative RNA splicing, the molecular mechanism underlying the alternative RNA splicing is not fully elucidated. Here, we analysed the proteins that interacted with the wild-type and K700E-mutated SF3B1 and found that the interactions of two RNA helicases, DDX42 and DDX46, with the mutated SF3B1 were reduced. Overexpression of DDX42 restored the decreased interaction between DDX42 and the K700E-mutated SF3B1, and suppressed some alternative RNA splicing associated with the SF3B1 mutation. Mutation that decreased the ATP hydrolysis activities of DDX42 abolished the suppressive effects of DDX42 on the alternative RNA splicing, suggesting that the ATP hydrolysis activity of DDX42 is involved in the mechanism of the altered RNA splicing associated with the SF3B1 mutation. Our study demonstrates an important function of the interaction between DDX42 and SF3B1 on regulating RNA splicing and revealed a potential role of DDX42 in the altered RNA splicing associated with the SF3B1 mutation.
虽然癌症相关的 SF3B1 突变导致了 RNA 的剪接，但 RNA 剪接的分子机制尚未完全阐明。在这里，我们分析了与野生型和 K700E 突变的 SF3B1 相互作用的蛋白质，发现两种 RNA 解旋酶 DDX42 和 DDX46 与突变 SF3B1 的相互作用减少了。DDX42 的过表达恢复了 DDX42 与 K700E 突变的 SF3B1 之间减少的相互作用，并抑制了与 SF3B1 突变相关的一些 RNA 的剪接。降低 DDX42 的 ATP 水解活性的突变消除了 DDX42 对 RNA 剪接的抑制作用，这表明 DDX42 的 ATP 水解活性参与了与 SF3B1 突变相关的 RNA 剪接的改变机制。我们的研究表明 DDX42 和 SF3B1 之间的相互作用在调节 RNA 剪接方面具有重要功能，并揭示了 DDX42 在与 SF3B1 突变相关的 RNA 剪接改变中的潜在作用。
