A mechanism underlying position-specific regulation of alternative splicing.
A mechanism underlying position-specific regulation of alternative splicing.
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DOI：
10.1093/nar/gkx901
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发表时间：
2017-12-01
影响因子：
14.9
通讯作者：
Makeyev EV
中科院分区：
文献类型：
--
作者：
Hamid FM;Makeyev EV
许多RNA结合蛋白，包括发育中大脑和肌肉剪接的主要调节因子，多聚嘧啶片段结合蛋白1（PTBP1），可以激活或抑制替代外显子，这取决于前体mRNA的募集位置。当结合上游或调节外显子内PTBP1往往会促进他们的跳跃，而结合到下游网站往往刺激包容。这种开关是如何在分子水平上协调的，人们还知之甚少。利用生物信息学和生物化学方法，我们表明PTBP 1与下游内含子序列的相互作用可以通过促进剪接体U1 snRNP与次优5 '剪接位点的高效对接来激活天然盒外显子。引人注目的是，引入上游PTBP1位点，这一电路导致一个强大的剪接抑制伴随着一个外显子的核糖核蛋白复合物与紧密结合的U1，但不是U2 snRNP的装配。我们的数据表明，PTBP1的一个更好的已知的抑制功能和其作为一个真正的剪接激活剂的作用之间的过渡的分子机制。更一般地说，我们认为，由RNA结合蛋白的单个RNA接触的功能结果受到广泛的上下文特异性调制。
Many RNA-binding proteins including a master regulator of splicing in developing brain and muscle, polypyrimidine tract-binding protein 1 (PTBP1), can either activate or repress alternative exons depending on the pre-mRNA recruitment position. When bound upstream or within regulated exons PTBP1 tends to promote their skipping, whereas binding to downstream sites often stimulates inclusion. How this switch is orchestrated at the molecular level is poorly understood. Using bioinformatics and biochemical approaches we show that interaction of PTBP1 with downstream intronic sequences can activate natural cassette exons by promoting productive docking of the spliceosomal U1 snRNP to a suboptimal 5′ splice site. Strikingly, introducing upstream PTBP1 sites to this circuitry leads to a potent splicing repression accompanied by the assembly of an exonic ribonucleoprotein complex with a tightly bound U1 but not U2 snRNP. Our data suggest a molecular mechanism underlying the transition between a better-known repressive function of PTBP1 and its role as a bona fide splicing activator. More generally, we argue that the functional outcome of individual RNA contacts made by an RNA-binding protein is subject to extensive context-specific modulation.
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影响因子：
14.9
作者：
Cartegni, L;Wang, JH;Krainer, AR
通讯作者：
Krainer, AR
影响因子：
4.5
作者：
Amir-Ahmady, B;Boutz, PL;Black, DL
通讯作者：
Black, DL
DOI：
10.1016/s0736-5748(00)00071-x
发表时间：
2001-02-01
影响因子：
1.8
作者：
Kishi, N;Tang, ZY;Matsuno, K
通讯作者：
Matsuno, K
影响因子：
5.3
作者：
Dittmar, Kimberly A.;Jiang, Peng;Carstens, Russell P.
通讯作者：
Carstens, Russell P.
影响因子：
64.5
作者：
Braunschweig U;Gueroussov S;Plocik AM;Graveley BR;Blencowe BJ
通讯作者：
Blencowe BJ