Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
Regulation of constitutive and alternative splicing by PRMT5 reveals a role for Mdm4 pre-mRNA in sensing defects in the spliceosomal machinery.
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DOI：
10.1101/gad.219899.113
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发表时间：
2013-09-01
影响因子：
10.5
通讯作者：
Guccione E
中科院分区：
文献类型：
--
作者：
Bezzi M;Teo SX;Muller J;Mok WC;Sahu SK;Vardy LA;Bonday ZQ;Guccione E
本研究探讨了假定的剪接调节因子和转录辅因子PRMT 5在哺乳动物发育中的作用。使用小鼠模型，Bezzi等人表明PRMT 5缺失通过其减少Sm蛋白甲基化的能力影响剪接。作者将Mdm 4前mRNA确定为关键的PRMT 5靶点; Mdm 4前mRNA感知剪接体机制中的缺陷，从而激活p53反应。这项研究揭示了PRMT 5在剪接中的新作用，并将Mdm 4前mRNA鉴定为潜在的抗癌靶点。在转录和转录后RNA加工水平上对基因表达的严格控制对哺乳动物的发育至关重要。我们在这里调查的作用蛋白质精氨酸甲基转移酶5（PRMT 5），一个公认的剪接调节因子和转录辅因子，在哺乳动物的发展。我们证明，选择性删除PRMT 5在神经干/祖细胞（NPC）导致小鼠出生后死亡。在分子水平上，PRMT 5的缺失导致Sm蛋白甲基化减少，异常组成性剪接，以及具有弱5′供体位点的特定mRNA的选择性剪接。有趣的是，这些mRNA的产物是调节细胞周期进程的几种蛋白质。我们确定Mdm 4作为这些关键的mRNA之一，感测剪接体机制中的缺陷，并转导信号激活p53反应，提供了在体内观察到的表型的机制解释。我们的数据表明，PRMT 5是哺乳动物剪接的主要调节因子，并揭示了Mdm 4前mRNA的新作用，可用于抗癌治疗。
This study investigates the role of the putative splicing regulator and transcriptional cofactor PRMT5 in mammalian development. Using mouse models, Bezzi et al. show that PRMT5 deletion affects splicing through its ability to reduce Sm protein methylation. The authors identify the Mdm4 pre-mRNA as a key PRMT5 target; Mdm4 pre-mRNA senses defects in the spliceosomal machinery and consequently activates the p53 response. This study uncovers a new role for PRMT5 in splicing and identifies Mdm4 pre-mRNA as a potential anti-cancer target. The tight control of gene expression at the level of both transcription and post-transcriptional RNA processing is essential for mammalian development. We here investigate the role of protein arginine methyltransferase 5 (PRMT5), a putative splicing regulator and transcriptional cofactor, in mammalian development. We demonstrate that selective deletion of PRMT5 in neural stem/progenitor cells (NPCs) leads to postnatal death in mice. At the molecular level, the absence of PRMT5 results in reduced methylation of Sm proteins, aberrant constitutive splicing, and the alternative splicing of specific mRNAs with weak 5′ donor sites. Intriguingly, the products of these mRNAs are, among others, several proteins regulating cell cycle progression. We identify Mdm4 as one of these key mRNAs that senses the defects in the spliceosomal machinery and transduces the signal to activate the p53 response, providing a mechanistic explanation of the phenotype observed in vivo. Our data demonstrate that PRMT5 is a master regulator of splicing in mammals and uncover a new role for the Mdm4 pre-mRNA, which could be exploited for anti-cancer therapy.
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影响因子：
4.6
作者：
Hameyer, Dorothe;Loonstra, Ate;Bockamp, Ernesto
通讯作者：
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影响因子：
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作者：
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通讯作者：
Matera, A. Gregory
影响因子：
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作者：
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通讯作者：
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影响因子：
8
作者：
Allende-Vega, N.;Dayal, S.;Saville, M. K.
通讯作者：
Saville, M. K.
影响因子：
9.2
作者：
Gonsalvez, Graydon B.;Rajendra, T. K.;Matera, A. Gregory
通讯作者：
Matera, A. Gregory