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Nature:发现整合选择性剪接与转录延伸的蛋白因子

来源:生物谷 2012-03-26 22:16

近日,来自英国癌症研究中心伦敦研究所的Jesper Q. Svejstrup等人做了一项关于能够整合转录延伸与mRNA剪接的功能因子的研究,结果发现了一种新的蛋白复合体DBIRD。相关论文在3月25日《自然》在线发表。

哺乳动物有限的基因却可以实现极其复杂的蛋白质组,选择性mRNA剪接是主要的原因。

剪接在空间和功能上都与转录相偶联,并被转录延伸效率所影响。当pre-mRNA从RNA聚合酶II(RNAPII)合成出来以后,通过装配形成信使核糖核蛋白(mRNP)颗粒,这是pre-mRNA的功能形式,也决定了成熟转录物的命运。

然而,能够联系mRNP颗粒与转录酶,并且整合转录延伸与mRNA剪接的功能因子还不明确。因此,研究人员描绘了人类染色体有关的mRNP颗粒的相互作用组。

这促使了研究人员去鉴定在肺癌1(DBC1)和ZNF326(与核mRNPs及DBC1相互作用的锌指蛋白)中缺失的蛋白,结果发现了一个新奇的蛋白复合物--DBIRD,它可以直接结合到RNAPII。

DBIRD主要调节嵌入在富含(A + T)DNA中外显子的选择性剪接,并出现在受到影响的外显子中。RNA干扰介导的DBIRD的损耗,导致了DBIRD在转录延伸尤其是包含受影响的外显子区域里出现区域特异性减少。

总的来说,这些结果表明:DBIRD复合物作为mRNP颗粒和RNAPII的一个连接体,整合了选择性剪接的调节与转录延伸。(生物谷Deepblue编译)

DBIRD complex integrates alternative mRNA splicing with RNA polymerase II transcript elongation

Pierre Close,Philip East, A. Barbara Dirac-Svejstrup, Holger Hartmann, Mark Heron, Sarah Maslen, Alain Chariot, Johannes S ding, Mark Skehe & Jesper Q. Svejstrup.

Alternative messenger RNA splicing is the main reason that vast mammalian proteomic complexity can be achieved with a limited number of genes.Splicing is physically and functionally coupled to transcription, and is greatly affected by the rate of transcript elongation. As the nascent pre-mRNA emerges from transcribing RNA polymerase II (RNAPII), it is assembled into a messenger ribonucleoprotein (mRNP) particle; this is the functional form of the nascent pre-mRNA and determines the fate of the mature transcript.However, factors that connect the transcribing polymerase with the mRNP particle and help to integrate transcript elongation with mRNA splicing remain unclear. Here we characterize the human interactome of chromatin-associated mRNP particles.This led us to identify deleted in breast cancer 1 (DBC1) and ZNF326 (which we call ZNF-protein interacting with nuclear mRNPs and DBC1 (ZIRD)) as subunits of a novel protein complex—named DBIRD—that binds directly to RNAPII.DBIRD regulates alternative splicing of a large set of exons embedded in (A + T)-rich DNA, and is present at the affected exons. RNA-interference-mediated DBIRD depletion results in region-specific decreases in transcript elongation, particularly across areas encompassing affected exons.Together, these data indicate that the DBIRD complex acts at the interface between mRNP particles and RNAPII, integrating transcript elongation with the regulation of alternative splicing.

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