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Transcription Dynamics Regulate Poly(A) Tails and Expression of the RNA Degradation Machinery to Balance mRNA Levels.
Molecular Cell ( IF 14.5 ) Pub Date : 2020-04-14 , DOI: 10.1016/j.molcel.2020.03.022 Boris Slobodin 1 , Anat Bahat 1 , Urmila Sehrawat 1 , Shirly Becker-Herman 2 , Binyamin Zuckerman 3 , Amanda N Weiss 1 , Ruiqi Han 4 , Ran Elkon 5 , Reuven Agami 4 , Igor Ulitsky 3 , Idit Shachar 2 , Rivka Dikstein 1
Molecular Cell ( IF 14.5 ) Pub Date : 2020-04-14 , DOI: 10.1016/j.molcel.2020.03.022 Boris Slobodin 1 , Anat Bahat 1 , Urmila Sehrawat 1 , Shirly Becker-Herman 2 , Binyamin Zuckerman 3 , Amanda N Weiss 1 , Ruiqi Han 4 , Ran Elkon 5 , Reuven Agami 4 , Igor Ulitsky 3 , Idit Shachar 2 , Rivka Dikstein 1
Affiliation
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Gene expression is regulated by the rates of synthesis and degradation of mRNAs, but how these processes are coordinated is poorly understood. Here, we show that reduced transcription dynamics of specific genes leads to enhanced m6A deposition, preferential activity of the CCR4-Not complex, shortened poly(A) tails, and reduced stability of the respective mRNAs. These effects are also exerted by internal ribosome entry site (IRES) elements, which we found to be transcriptional pause sites. However, when transcription dynamics, and subsequently poly(A) tails, are globally altered, cells buffer mRNA levels by adjusting the expression of mRNA degradation machinery. Stress-provoked global impediment of transcription elongation leads to a dramatic inhibition of the mRNA degradation machinery and massive mRNA stabilization. Accordingly, globally enhanced transcription, such as following B cell activation or glucose stimulation, has the opposite effects. This study uncovers two molecular pathways that maintain balanced gene expression in mammalian cells by linking transcription to mRNA stability.
中文翻译：
转录动力学调节 Poly(A) 尾部和 RNA 降解机制的表达以平衡 mRNA 水平。
基因表达受 mRNA 合成和降解速率的调节，但这些过程如何协调却知之甚少。在这里，我们表明特定基因的转录动力学降低会导致 m6A 沉积增强、CCR4-Not 复合物的优先活性、缩短的 poly(A) 尾巴以及相应 mRNA 的稳定性降低。这些影响也由内部核糖体进入位点 (IRES) 元件发挥，我们发现它们是转录暂停位点。然而，当转录动力学以及随后的 poly(A) 尾部发生全局变化时，细胞会通过调整 mRNA 降解机制的表达来缓冲 mRNA 水平。压力引起的转录延伸的全局障碍导致 mRNA 降解机制的显着抑制和大量的 mRNA 稳定。因此，全局增强的转录，例如在 B 细胞激活或葡萄糖刺激后，具有相反的效果。该研究揭示了通过将转录与 mRNA 稳定性联系起来，在哺乳动物细胞中维持平衡基因表达的两种分子途径。
更新日期：2020-04-14
中文翻译：
转录动力学调节 Poly(A) 尾部和 RNA 降解机制的表达以平衡 mRNA 水平。
基因表达受 mRNA 合成和降解速率的调节，但这些过程如何协调却知之甚少。在这里，我们表明特定基因的转录动力学降低会导致 m6A 沉积增强、CCR4-Not 复合物的优先活性、缩短的 poly(A) 尾巴以及相应 mRNA 的稳定性降低。这些影响也由内部核糖体进入位点 (IRES) 元件发挥，我们发现它们是转录暂停位点。然而，当转录动力学以及随后的 poly(A) 尾部发生全局变化时，细胞会通过调整 mRNA 降解机制的表达来缓冲 mRNA 水平。压力引起的转录延伸的全局障碍导致 mRNA 降解机制的显着抑制和大量的 mRNA 稳定。因此，全局增强的转录，例如在 B 细胞激活或葡萄糖刺激后，具有相反的效果。该研究揭示了通过将转录与 mRNA 稳定性联系起来，在哺乳动物细胞中维持平衡基因表达的两种分子途径。
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