Splicing is initiated by a productive interaction between the pre-mRNA and the U1 snRNP, in which a short RNA duplex is established between the 5′ splice site of a pre-mRNA and the 5′ end of the U1 snRNA. A long-standing puzzle has been why the AU dincucleotide at the 5′-end of the U1 snRNA is highly conserved, despite the absence of an apparent role in the formation of the duplex. To explore this conundrum, we varied this AU dinucleotide into all possible permutations and analyzed the resulting molecular consequences. This led to the unexpected findings that the AU dinucleotide dictates the optimal binding of cap-binding complex (CBC) to the 5′ end of the nascent U1 snRNA, which ultimately influences the utilization of U1 snRNP in splicing. Our data also provide a structural interpretation as to why the AU dinucleotide is conserved during evolution.

中文翻译：

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新生U1 snRNA 5'末端的保守AU二核苷酸经过优化，可与核帽结合复合物相互作用

剪接是通过pre-mRNA与U1 snRNP之间的生产性相互作用启动的，其中在pre-mRNA的5'剪接位点与U1 snRNA的5'末端之间建立了短RNA双链体。一个长期存在的难题是，尽管在双链体的形成中没有明显的作用，但为什么U1 snRNA 5'端的AU核苷酸是高度保守的。为了探索这个难题，我们将该AU二核苷酸改变为所有可能的排列，并分析了由此产生的分子后果。这导致了意想不到的发现，即AU二核苷酸决定了帽结合复合物（CBC）与新生U1 snRNA 5'末端的最佳结合，这最终影响了U1 snRNP在剪接中的利用。