How Slow RNA Polymerase II Elongation Favors Alternative Exon Skipping
How Slow RNA Polymerase II Elongation Favors Alternative Exon Skipping
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DOI：
10.1016/j.molcel.2014.03.044
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发表时间：
2014-05-22
期刊：
影响因子：
16
通讯作者：
Kornblihtt, Alberto R.
中科院分区：
文献类型：
--
作者：
Dujardin, Gwendal;Lafaille, Celina;Kornblihtt, Alberto R.
剪接在功能上与转录耦合，将 RNA 聚合酶 II (Pol II) 延伸速率与剪接因子识别不同强度的剪接位点 (ss) 的能力联系起来。在大多数情况下，缓慢的 Pol II 延伸可以识别较弱的剪接位点，从而导致更多的替代外显子包含在内。使用 CFTR 替代外显子 9 (E9) 作为模型，我们在此表明，减缓延伸也可以通过促进负因子 ETR-3 募集到 E9 3' 剪接位点的 UG 重复上而导致外显子跳跃，这会从重叠的多嘧啶束中取代组成型剪接因子 U2AF65。削弱 E9 5' ss 会增加 ETR-3 在 3' ss 处的结合以及随后的 E9 跳跃，而加强 5' ss 的使用则具有相反的效果。这表明 5' ss 共转录出现的延迟促进了 ETR-3 的募集并随后抑制了 E9 包含。
Splicing is functionally coupled to transcription, linking the rate of RNA polymerase II (Pol II) elongation and the ability of splicing factors to recognize splice sites (ss) of various strengths. In most cases, slow Pol II elongation allows weak splice sites to be recognized, leading to higher inclusion of alternative exons. Using CFTR alternative exon 9 (E9) as a model, we show here that slowing down elongation can also cause exon skipping by promoting the recruitment of the negative factor ETR-3 onto the UG-repeat at E9 3' splice site, which displaces the constitutive splicing factor U2AF65 from the overlapping polypyrimidine tract. Weakening of E9 5' ss increases ETR-3 binding at the 3' ss and subsequent E9 skipping, whereas strengthening of the 5' ss usage has the opposite effect. This indicates that a delay in the cotranscriptional emergence of the 5' ss promotes ETR-3 recruitment and subsequent inhibition of E9 inclusion.