A unified allosteric/torpedo mechanism for transcriptional termination on human protein-coding genes
A unified allosteric/torpedo mechanism for transcriptional termination on human protein-coding genes
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DOI：
10.1101/gad.332833.119
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发表时间：
2020-01-01
影响因子：
10.5
通讯作者：
West, Steven
中科院分区：
文献类型：
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作者：
Eaton, Joshua D.;Francis, Laura;West, Steven
30 年来，变构模型和鱼雷模型一直被用来解释蛋白质编码基因上的转录如何终止。前者通过转录复合物中的构象变化引发终止，后者表明多聚腺苷酸信号（PAS）处理下游产物的降解很重要。在这里，我们描述了一种结合了两种模型特征的单一机制。我们表明，快速消除 CPSF73 可以完全消除终止，这会导致全基因组范围内非常广泛的转录通读。这是因为 CPSF73 在延伸复合物修饰的上游发挥作用，并为 XRN2 鱼雷提供入口位点。 XRN2 的快速耗尽丰富了这些事件，我们证明这些事件是由蛋白磷酸酶 1 (PP1) 活性支撑的，在 XRN2 不存在的情况下，对其抑制可延长通读时间。我们的结果表明了一种组合的变构/鱼雷机制，其中终止区域上聚合酶的 PP1 依赖性减慢有利于 PAS 处理后 XRN2 的追踪/捕获。
The allosteric and torpedo models have been used for 30 yr to explain how transcription terminates on protein-coding genes. The former invokes termination via conformational changes in the transcription complex and the latter proposes that degradation of the downstream product of poly(A) signal (PAS) processing is important. Here, we describe a single mechanism incorporating features of both models. We show that termination is completely abolished by rapid elimination of CPSF73, which causes very extensive transcriptional readthrough genome-wide. This is because CPSF73 functions upstream of modifications to the elongation complex and provides an entry site for the XRN2 torpedo. Rapid depletion of XRN2 enriches these events that we show are underpinned by protein phosphatase 1 (PP1) activity, the inhibition of which extends readthrough in the absence of XRN2. Our results suggest a combined allosteric/torpedo mechanism, in which PP1-dependent slowing down of polymerases over termination regions facilitates their pursuit/capture by XRN2 following PAS processing.