A microRNA conundrum: to degrade or keep a translationally repressed target mRNA?

分子生物学的中心教条规定，DNA通过“信使RNA翻译”的过程来制造信使RNA，而信使RNA通过“信使RNA翻译”来制造蛋白质。对蛋白质生产的精确调控对生物体的生存至关重要，这是通过控制DNA产生多少mRNAs，信使核糖核酸在细胞中持续多长时间(信使核糖核酸衰减率)以及每个信使核糖核酸产生多少蛋白质(转换率)来实现的。MicroRNAs是一类重要的小RNA，在这一背景下发挥着重要作用。人类基因组编码约2000个microRNAs，据估计，microRNAs可能参与调控多达30%的人类蛋白质编码mRNAs的表达。因此，microRNAs在维持生物体的生存能力方面发挥着重要作用。相比之下，microRNAs功能的失调与癌症等各种疾病有关。microRNAs与其靶mRNAs结合，并通过永久性地降解mRNAs或简单地以可逆的方式抑制mRNAs的翻译来中和它们。MicroRNAs阻断mRNA翻译的能力为细胞提供了一个非常健壮和灵活的控制机制。事实上，存储只被microRNAs翻译抑制的mRNAs，使细胞能够在需要时迅速恢复产生所需的蛋白质，例如在病毒感染时产生增强免疫的细胞因子。另一方面，由microRNAs诱导的信使核糖核酸的降解是不可逆的，如果细胞需要产生有问题的蛋白质，它必须通过从DNA重新合成信使核糖核酸来重新开始，这既耗时又耗能。因此，microRNAs在阻断翻译(可逆)和降解信使核糖核酸(不可逆)之间取得适当的平衡，对于维持正常的细胞功能和活的生物体的生存非常重要。然而，尽管许多研究人员做出了集体努力，但目前我们对microRNAs如何发挥作用的了解仍存在重大差距。具体地说，目前尚不清楚microRNA如何决定是否应该永久降解或仅可逆地阻止该mRNA的翻译。我已经发现了证据表明存在一种新的机制，由两种名为ZC3H7A和ZC3H7B的蛋白质协调，这是决定暂时阻止翻译还是永久地通过microRNAs降解mRNAs的关键决定因素。我的发现进一步表明，这一机制的最佳功能对数千个基因的正常表达至关重要，这表明它在维持生物的生存能力方面具有重要作用。因此，在这项研究中，我试图准确地了解这一机制是如何在基础分子水平上控制microRNAs的功能的。我期待这一发现科学计划将为microRNAs调控基因表达的机制提供新的见解。此外，它的结果最终将有利于对许多生物学过程和疾病的研究，这些过程和疾病受到microRNAs的影响，如抗病毒免疫系统、糖尿病和癌症。

The central dogma of molecular biology dictates that DNA makes messenger RNA (mRNA) and mRNA makes protein via the process of "mRNA translation". Precise regulation of the production of proteins is essential for the viability of living organisms and is achieved through controlling how many mRNAs are produced from DNA, how long the mRNA can last in the cell (mRNA decay rate) and how many proteins are made from each mRNA (translation rate). MicroRNAs are an important class of small RNAs that play a major role in this context. The human genome encodes ~2000 microRNAs and it has been estimated that microRNAs may be involved in governing the expression of up to 30% of human protein-coding mRNAs. Hence, microRNAs play a major role in the maintenance of the viability of living organisms. In contrast, dysregulation of microRNAs' function has been linked to various diseases such as cancer.MicroRNAs bind to their target mRNAs and neutralize them either by permanently degrading the mRNA or by simply repressing the mRNA translation in a reversible manner. The ability of microRNAs to block mRNA translation provides the cell with a very robust and agile control mechanism. Indeed, storing mRNAs that are only translationally repressed by microRNAs allows the cells to rapidly resume the production of the desired proteins when needed, for example the production of immune-boosting cytokines in case of a viral infection. On the other hand, degradation of the mRNA induced by microRNAs is not reversible and if the cell needs to produce the protein in question, it has to start over by re-synthesising the mRNA from the DNA, which is time and energy consuming. Hence, it is very important for the maintenance of proper cell function and the viability of living organisms that microRNAs attain the right balance between blocking translation (which is reversible) and degrading the mRNA (which is irreversible). However, despite the collective efforts of many researchers, there are currently significant gaps in our knowledge of how microRNAs function. Specifically, it is not known how microRNAs decide if a target mRNA should be permanently degraded or only reversibly block the translation of that mRNA.I have discovered evidence that indicate the presence of a novel mechanism, orchestrated by two proteins called ZC3H7A and ZC3H7B, which is the key determinant in the decision to temporarily block the translation or permanently degrade the mRNA by microRNAs. My findings further indicate that the optimal function of this mechanism is critical for normal expression of thousands of genes, suggesting it has an important role in maintaining the viability of living organisms. Therefore, in this study, I seek to understand precisely how this mechanism works at the fundamental molecular level to controls the function of microRNAs.I anticipate that this discovery science project will provide novel insights into the mechanism of regulation of gene expression by microRNAs. In addition, its outcomes will ultimately benefit research into numerous biological processes and diseases that are affected by microRNAs such as the anti-viral immune system, diabetes, and cancer.