DBIRD integrates alternative mRNA splicing with RNA polymerase II transcript elongation
DBIRD integrates alternative mRNA splicing with RNA polymerase II transcript elongation
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DBIRD 将选择性 mRNA 剪接与 RNA 聚合酶 II 转录本延伸相结合
DOI：
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发表时间：
2012
期刊：
影响因子：
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通讯作者：
J. Svejstrup
中科院分区：
文献类型：
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作者：
Pierre Close;Philip East;A. B. Dirac;Holger Hartmann;Mark Heron;Sarah Maslen;A. Chariot;Johannes Söding;M. Skehel;J. Svejstrup
选择性的信使核糖核酸剪接是哺乳动物蛋白质组的复杂性可以用有限数量的基因来实现的主要原因。剪接与转录在物理和功能上是耦合的，并受到转录延长速度的很大影响。当新生的前mRNA从转录RNA聚合酶II(RNAPII)中出现时，它被组装成信使核糖核蛋白(MRNP)颗粒，这是它的功能形式，并决定成熟转录的命运4。然而，将转录聚合酶与mRNP颗粒联系起来并帮助整合转录延长和mRNA剪接的因素仍然不清楚。在这里，我们描述了染色质相关的mRNP颗粒的相互作用组。这导致了在乳腺癌1中缺失(DBC1)和一种我们命名为ZIRD的蛋白质作为一种新的蛋白质复合体的亚单位，命名为DBIRD，它直接与RNAPII结合。DBIRD调节大量嵌入富含A/T的DNA的外显子的选择性剪接，并存在于受影响的外显子中。RNAi介导的DBIRD缺失会导致区域特异性转录延长的减少，特别是在包含受影响外显子的区域。总之，这些数据表明DBIRD复合体作用于mRNP颗粒和RNAPII之间的界面，将转录延长与选择性剪接的调节结合在一起。MRNP颗粒的组成一直是许多研究的主题，使用了各种方法(例如，见参考文献5和其中的参考文献)。可能有不同类型的mRNP颗粒，具有不同的组成和相互作用伙伴。我们的通信和材料请求应发送至J.Q.S.(j.svejstrup@‡.org.uk)。作者贡献者P.C.和A.B.D.S.进行了实验，S.M.和M.S.进行了质谱分析。P.E.、H.H.、M.H.和J.S.进行了生物信息学分析。P.C.和J.Q.S.设计了这项研究，分析了实验数据，并撰写了论文。所有作者都讨论了结果，并对手稿进行了评论。
Alternative mRNA splicing is the main reason 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 elongation1,2,3. As the nascent premRNA emerges from transcribing RNA polymerase II (RNAPII), it is assembled into a messenger ribonucleoprotein (mRNP) particle which is its functional form and determines the fate of the mature transcript4. However, factors that connect the transcribing polymerase with the mRNP particle and help integrate transcript elongation with mRNA splicing remain obscure. Here, we characterized the interactome of chromatin-associated mRNP particles. This led to the identification of Deleted in Breast Cancer 1 (DBC1) and a protein we named ZIRD as subunits of a novel protein complex, named DBIRD, which 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. RNAi-mediated DBIRD depletion results in region-specific decreases in transcript elongation, particularly across areas encompassing affected exons. Together, these data indicate that DBIRD complex acts at the interface between mRNP particles and RNAPII, integrating transcript elongation with the regulation of alternative splicing. The composition of mRNP particles has been the subject of a number of studies, using a variety of approaches (see, for example, ref5 and references therein). There are likely to be different types of mRNP particles with distinct compositions and interaction partners. We ‡Correspondence and requests for material should be addressed to J.Q.S. (j.svejstrup@cancer.org.uk).. Author Contributions P.C. and A.B.D.S. performed experiments, and S.M. and M.S. did mass spec analyses. P.E., H.H., M.H., and J.S. performed bioinformatic analyses. P.C. and J.Q.S. designed the study, analyzed the experimental data, and wrote the paper. All authors discussed the results and commented on the manuscript.
“共转录性”：转录延伸复合体作为核交易的纽带。
影响因子：
16
作者：
Perales, Roberto;Bentley, David
通讯作者：
Bentley, David
影响因子：
16
作者：
Close, Pierre;Hawkes, Nicola;Chariot, Alain
通讯作者：
Chariot, Alain