Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1.
Regulation of mRNA Levels by Decay-Promoting Introns that Recruit the Exosome Specificity Factor Mmi1.
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DOI：
10.1016/j.celrep.2015.11.026
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发表时间：
2015-12-22
期刊：
影响因子：
8.8
通讯作者：
Vasiljeva L
中科院分区：
文献类型：
--
作者：
Kilchert C;Wittmann S;Passoni M;Shah S;Granneman S;Vasiljeva L
在真核细胞中，低效剪接令人惊讶地普遍，并导致带有保留内含子的转录本的降解。前mRNAs如何致力于核衰变尚不清楚。在这里，我们揭示了一种机制，通过这种机制，特定的含有内含子的转录本被定位于分裂酵母的核降解。这些促进衰退的内含子中的序列元件共转录地招募外体特异性因子Mmi1，从而诱导未剪接前体的降解，并导致剪接mRNA水平的降低。这一机制负向调节RNA解旋酶DDX5/Dbp2的水平，以促进细胞在应激反应中的存活。相反，通过共转录剪接快速移除促进衰退的内含子可以阻止Mmi1的招募，并缓解负向表达调控。我们认为促进衰变的内含子促进了基因表达的调节。基于对多个额外的Mmi1靶点的鉴定，包括mRNAs、长非编码RNAs和sn/snoRNAs，我们建议通过转录降解在Mmi1的RNA调控中发挥普遍作用。“促衰变”内含子含有激活核mRNA的序列衰变促衰变内含子的快速剪接阻止衰变因子的募集相反，在胁迫下增加内含子的保留会导致低基因表达，这种机制在胁迫下促进细胞存活的低效剪接是常见的，并导致带有保留内含子的转录产物的降解。Kilchert等人。表明“促进衰变”的内含子含有招募RNA衰变因子的位点。尽管快速剪接排除了核监视机制的招募，但内含子保留率的增加会减少基因表达，从而促进细胞在应激状态下的存活。
In eukaryotic cells, inefficient splicing is surprisingly common and leads to the degradation of transcripts with retained introns. How pre-mRNAs are committed to nuclear decay is unknown. Here, we uncover a mechanism by which specific intron-containing transcripts are targeted for nuclear degradation in fission yeast. Sequence elements within these “decay-promoting” introns co-transcriptionally recruit the exosome specificity factor Mmi1, which induces degradation of the unspliced precursor and leads to a reduction in the levels of the spliced mRNA. This mechanism negatively regulates levels of the RNA helicase DDX5/Dbp2 to promote cell survival in response to stress. In contrast, fast removal of decay-promoting introns by co-transcriptional splicing precludes Mmi1 recruitment and relieves negative expression regulation. We propose that decay-promoting introns facilitate the regulation of gene expression. Based on the identification of multiple additional Mmi1 targets, including mRNAs, long non-coding RNAs, and sn/snoRNAs, we suggest a general role in RNA regulation for Mmi1 through transcript degradation. “Decay-promoting” introns contain sequences that activate nuclear mRNA decay Fast splicing of decay-promoting introns prevents recruitment of decay factors In contrast, increased intron retention under stress results in low gene expression This mechanism acts to promote cell survival in response to stress Inefficient splicing is common and leads to the degradation of transcripts with retained introns. Kilchert et al. show that “decay-promoting” introns harbor sites that recruit RNA decay factors. Although fast splicing precludes recruitment of the nuclear surveillance machinery, increased intron retention reduces gene expression, which can promote cell survival under stress.