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

microRNA 难题：降解或保留翻译抑制的目标 mRNA？

• 批准号: BB/W008165/1
• 负责人: Seyed Mehdi Jafarnejad
• 金额: $ 61.74万
• 依托单位: Queen's University Belfast
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2022
• 资助国家: 英国
• 起止时间: 2022 至 无数据
• 项目状态: 未结题
• 来源: https://gtr.ukri.org/projects?ref=BB%2FW008165%2F1
• 关键词: microRNA; conundrum; degrade; keep; translationally

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.

分子生物学的核心规律是DNA通过“mRNA翻译”的过程制造信使RNA (mRNA)， mRNA通过“mRNA翻译”的过程制造蛋白质。精确调节蛋白质的产生对生物体的生存能力至关重要，通过控制DNA产生多少mRNA， mRNA在细胞中持续多长时间（mRNA衰变率）以及每个mRNA产生多少蛋白质（翻译率）来实现。microrna是一类重要的小rna，在这方面起着重要作用。人类基因组编码约2000个microrna，据估计，microrna可能参与控制多达30%的人类蛋白质编码mrna的表达。因此，microrna在维持生物体的生存能力方面发挥着重要作用。相反，microrna功能失调与癌症等多种疾病有关。microrna与它们的靶mRNA结合，并通过永久降解mRNA或以可逆的方式简单地抑制mRNA的翻译来中和它们。microrna阻断mRNA翻译的能力为细胞提供了一种非常强大和灵活的控制机制。事实上，储存仅被microrna翻译抑制的mrna，可以使细胞在需要时迅速恢复所需蛋白质的生产，例如，在病毒感染的情况下产生免疫增强细胞因子。另一方面，由microrna诱导的mRNA的降解是不可逆转的，如果细胞需要产生有问题的蛋白质，它必须重新从DNA中合成mRNA，这是费时又耗力的。因此，microrna在阻断翻译（可逆）和降解mRNA（不可逆）之间达到适当的平衡，对于维持正常的细胞功能和生物体的生存能力非常重要。然而，尽管有许多研究人员的共同努力，目前我们对microrna功能的了解仍存在重大差距。具体来说，目前尚不清楚microRNAs如何决定目标mRNA是否应该永久降解或仅可逆地阻断该mRNA的翻译。我已经发现证据表明存在一种新机制，由两种名为ZC3H7A和ZC3H7B的蛋白质精心策划，这是决定暂时阻断翻译或永久降解mRNA的关键决定因素。我的研究结果进一步表明，这种机制的最佳功能对数千种基因的正常表达至关重要，这表明它在维持生物体的生存能力方面发挥着重要作用。因此，在本研究中，我试图准确地理解这种机制如何在基本分子水平上控制microrna的功能。我期待这一发现科学项目将为microRNAs调控基因表达的机制提供新的见解。此外，其结果最终将有利于研究受microrna影响的许多生物过程和疾病，如抗病毒免疫系统、糖尿病和癌症。

项目成果

SARS-CoV-2 impairs interferon production via NSP2-induced repression of mRNA translation.

• DOI: 10.1073/pnas.2204539119
• 发表时间: 2022-08-09
• 期刊: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• 影响因子: 11.1
• 作者: Xu, Zhang;Choi, Jung-Hyun;Dai, David L.;Luo, Jun;Ladak, Reese Jalal;Li, Qian;Wang, Yimeng;Zhang, Christine;Wiebe, Shane;Liu, Alex C. H.;Ran, Xiaozhuo;Yang, Jiaqi;Naeli, Parisa;Garzia, Aitor;Zhou, Lele;Mahmood, Niaz;Deng, Qiyun;Elaish, Mohamed;Lin, Rongtuan;Mahal, Lara K.;Hobman, Tom C.;Pelletier, Jerry;Alain, Tommy;Vidal, Silvia M.;Duchaine, Thomas;Mazhab-Jafari, Mohammad T.;Mao, Xiaojuan;Jafarnejad, Seyed Mehdi;Sonenberg, Nahum
• 通讯作者: Sonenberg, Nahum

Repression of mRNA translation initiation by GIGYF1 via blocking the eIF3-eIF4G1 interaction

• DOI: 10.1101/2023.10.14.562322
• 发表时间: 2023-10
• 期刊: bioRxiv
• 作者: Jung-Hyun Choi;Jun Luo;Geoffrey G. Hesketh;Shuyue Guo;Angelos Pistofidis;Reese Jalal Ladak;Yuxin An;Tommy Alain;T. Schmeing;A. Gingras;T. Duchaine;Xu Zhang;Nahum Sonenberg;S. M. Jafarnejad

The SARS-CoV-2 protein NSP2 enhances microRNA-mediated translational repression.

• DOI: 10.1242/jcs.261286
• 发表时间: 2023-10-01
• 期刊: Journal of cell science
• 影响因子: 4

Mechanisms of impairment of interferon production by SARS-CoV-2.

• DOI: 10.1042/bst20221037
• 发表时间: 2023-06-28
• 期刊: Biochemical Society transactions
• 影响因子: 3.9