Kuś Krzysztof, Carrique Loic, Kecman Tea, Fournier Marjorie, Hassanein Sarah Sayed, Aydin Ebru, Kilchert Cornelia, Grimes Jonathan M, Vasiljeva Lidia
Department of Biochemistry, University of Oxford, Oxford, United Kingdom.
Division of Structural Biology, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, United Kingdom.
Nat Commun. 2025 Jan 2;16(1):10. doi: 10.1038/s41467-024-55063-7.
Precursor messenger RNA (pre-mRNA) is processed into its functional form during RNA polymerase II (Pol II) transcription. Although functional coupling between transcription and pre-mRNA processing is established, the underlying mechanisms are not fully understood. We show that the key transcription termination factor, RNA exonuclease Xrn2 engages with Pol II forming a stable complex. Xrn2 activity is stimulated by Spt5 to ensure efficient degradation of nascent RNA leading to Pol II dislodgement from DNA. Our results support a model where Xrn2 first forms a stable complex with the elongating Pol II to achieve its full activity in degrading nascent RNA revising the current 'torpedo' model of termination, which posits that RNA degradation precedes Xrn2 engagement with Pol II. Spt5 is also a key factor that attenuates the expression of non-coding transcripts, coordinates pre-mRNA splicing and 3'-end processing. Our findings indicate that engagement with the transcribing Pol II is an essential regulatory step modulating the activity of RNA enzymes such as Xrn2, thus advancing our understanding of how RNA maturation is controlled during transcription.
前体信使核糖核酸（前体mRNA）在RNA聚合酶II（Pol II）转录过程中被加工成其功能形式。尽管转录和前体mRNA加工之间的功能偶联已被确立，但其潜在机制尚未完全了解。我们发现关键的转录终止因子RNA核酸外切酶Xrn2与Pol II结合形成一个稳定的复合物。Spt5刺激Xrn2的活性，以确保新生RNA的有效降解，从而导致Pol II从DNA上脱离。我们的结果支持这样一个模型：Xrn2首先与延伸中的Pol II形成稳定复合物，以在降解新生RNA方面实现其全部活性，这修正了当前的终止“鱼雷”模型，该模型认为RNA降解先于Xrn2与Pol II结合。Spt5也是一个关键因子，可减弱非编码转录本的表达，协调前体mRNA剪接和3'端加工。我们的研究结果表明，与正在转录的Pol II结合是调节RNA酶（如Xrn2）活性的一个关键调控步骤，从而增进了我们对转录过程中RNA成熟如何被控制的理解。
