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

点击翻译按钮获取中文摘要

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.