Evolutionarily conserved autoregulation of alternative pre-mRNA splicing by ribosomal protein L10a.
Evolutionarily conserved autoregulation of alternative pre-mRNA splicing by ribosomal protein L10a.
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DOI：
10.1093/nar/gkw152
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发表时间：
2016-07-08
影响因子：
14.9
通讯作者：
Kuroyanagi H
中科院分区：
文献类型：
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作者：
Takei S;Togo-Ohno M;Suzuki Y;Kuroyanagi H
前体mRNA的选择性剪接可以通过产生由无义介导的mRNA衰变（NMD）快速降解的非生产性mRNA来调节蛋白质编码基因的表达。选择性剪接结合NMD（AS-NMD）直接调控的基因中有许多与RNA代谢有关，但在体内AS-NMD调控的基因库尚待确定。在这里，我们分析了秀丽隐杆线虫野生型和NMD缺陷突变株的转录组数据，并证明82个细胞质核糖体蛋白（rp）基因中的8个产生了无效的剪接mRNA。敲低的8个RP基因中的任何一个都对自身转录本的选择性剪接产生了动态和补偿性影响，并对其他RP基因产生了相反的影响。线虫中的大亚基蛋白L10 a（RPL-1）直接特异性地结合到其自身前体mRNA中的两个5′剪接位点之间的进化上保守的39-nt延伸段（L10 ARE），以切换剪接位点选择。此外，L10 ARE介导的L10 a编码基因的剪接自动调节在脊椎动物中是保守的。这些结果表明，L10 a是一种进化上保守的剪接调节因子，并且在体内前体mRNA剪接水平调节rp基因亚组的稳态。
Alternative splicing of pre-mRNAs can regulate expression of protein-coding genes by generating unproductive mRNAs rapidly degraded by nonsense-mediated mRNA decay (NMD). Many of the genes directly regulated by alternative splicing coupled with NMD (AS-NMD) are related to RNA metabolism, but the repertoire of genes regulated by AS-NMD in vivo is to be determined. Here, we analyzed transcriptome data of wild-type and NMD-defective mutant strains of the nematode worm Caenorhabditis elegans and demonstrate that eight of the 82 cytoplasmic ribosomal protein (rp) genes generate unproductively spliced mRNAs. Knockdown of any of the eight rp genes exerted a dynamic and compensatory effect on alternative splicing of its own transcript and inverse effects on that of the other rp genes. A large subunit protein L10a, termed RPL-1 in nematodes, directly and specifically binds to an evolutionarily conserved 39-nt stretch termed L10ARE between the two alternative 5′ splice sites in its own pre-mRNA to switch the splice site choice. Furthermore, L10ARE-mediated splicing autoregulation of the L10a-coding gene is conserved in vertebrates. These results indicate that L10a is an evolutionarily conserved splicing regulator and that homeostasis of a subset of the rp genes are regulated at the level of pre-mRNA splicing in vivo.