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microRNA a Small but Important Regulator


You may know the role of RNA in the central dogma: DNA makes RNA makes proteins. But RNA is an amazing molecule that is capable of so much more. There are so many types of RNAs besides the most commonly known RNAs involved in translation: mRNA and tRNA. For instance, microRNAs (miRNAs) are one such fascinating yet lesser known type of RNA.  These small RNA molecules are “non-coding” RNAs. This just means they are not translated into proteins. Instead, miRNAs regulate gene expression at the post-transcriptional level, after the DNA has been transcribed into mRNA. This means that less of the protein encoded for by that gene will be produced. This regulatory process is known as post-transcriptional “gene silencing”. Many miRNAs play important roles in development and can be expressed in a tissue specific manner. For example, miRNAs are important in in morphogenesis, the process by which a developing organism begins to take shape through spatial distribution and organization of cells and temporal control of gene expression.

miRNAs are able to carry out their regulatory function as part of a  larger complex called the RNA-induced silencing complex (RISC). The main components of the miRISC are the miRNA and an Argonaute protein. DICER protein is integral to miRNA biogenesis and RISC loading, helping process pre-miRNA into miRNA. Once loaded onto a RISC and bound to Argonaute microRNAs identify the target mRNA for repression/degradation via base pairing where mRNA sequences that have sequences of nucleotides that match up to a certain degree with the microRNA sequence. microRNAs can accomplish post-transcriptional regulation through both cleavage and non-cleaving translational repression. In fact, the degree of complementation between the microRNA and the target mRNA strand determines whether cleavage or non-cleaving repression occurs.
Figure 1. Human Argonaute-2-miR-20a complex:
A structure of the human argonaute 2 protein bound to
miRNA. Image created with PDB: ID 4F3T (associated
publication: Elkayam et al. 2012.)
Figure 2. Structure of Thermus thermophilus Argonaute bound to guide DNA and 19-mer target DNA where the guide DNA mimics the miRNA and the target DNA
performs the role of the target mRNA. Image created
with PDB ID: 4NCB (associated publication:
Sheng et al. 2013)
The mechanism by which microRNA and the RISC can prevent or lessen translation of the target mRNA is not completely known. Multiple and not necessarily exclusive mechanisms for microRNA, and therefore miRISC, non-slicing translational repression have been proposed including: 1) recruitment of translational inhibitors 2) spatial separation of translation components and 3) accelerated removal of the poly-A tail (deadenylation) and the 5’ G-cap structure (decapping), therefore accelerating mRNA decay. The splicing action of miRISC is carried out by the argonaute protein with the possible involvement of deadenylation (removal of the poly-A tail). As well as, exonucleolytic digestion, which is when the enzyme exonuclease cleaves away nucleotides from the end of the chain one at a time.
Figure 3. Diagram of the splicing and non-splicing miRNA induced translational repression. Made by author.

One example of this fascinating class of RNAs is miR-1. This miRNA is important for the development and maintenance of skeletal and cardiac muscle (Zhao et al. 2005). A recent study has highlighted that miR-1 expression, also suppresses tumor cell proliferation in colorectal cancer (Xu et al . 2017) Xu et al. first showed that miR-1 was expressed more weakly in colorectal cancer cell lines indicating the potential for miR-1 to play some role in suppressing cancer cell proliferation. Cancerous cells have a way of rewiring their metabolism to support rapid proliferation and survivability. Xu et al. further showed that over expression of miR-1 significantly decreased the ability of the cancerous cells to perform this alternate metabolic strategy, and therefore inhibited cell proliferation. miR-1 regulates tumor cell proliferation through the miRNA pathway, inhibiting the expression of genes that allow for the alternate metabolic pathway.

The ramifications of miRNAs on health, such as miR-1 and colorectal cancer, present an intriguing therapeutic potential. Using identified miRNAs to help inhibit expression of detrimental genes may prove to be advantageous therapeutic option. No matter what outcome that research has however, the importance of microRNAs in gene regulation and on our health and development as a whole is indisputable.

References:
E. Elkayam, C.D. Huhn, A Tocilj, A.D. Haase, E.M. Greene, G.J. Hannon, L. Joshua-Tor. “The structure of human argonaute-2 in complex with miR-20a.” Cell 150(1)(2012), pp. 100-110. https://doi.org/10.1016/j.cell.2012.05.017
L. MacFarlane, P. Murphy. “MicroRNA: Biogenesis, Function and Role in Cancer.” Curr Gen. 11(7) (2010)l, pp. 537-561.
G. Sheng, H. Zhao, J. Wang, Y. Rao, W. Tian, D.C.Swarts, J. Oost, D.J. Patel, Y. Wang. “Structure-based cleavage mechanism of Thermus thermophilus Argonaute DNA guide strand-mediated DNA target cleavage.” PNAS 111(2) (2014) pp. 6520657. https://doi.org/10.1073/pnas.1321032111
F. Waheid et al. “MicroRNAs: Synthesis, mechanism, function, and recent trials.” BBA. 1803.11 (2010), pp. 1231-1243.
X. Wanfu, et al. "MiR-1 Suppresses Tumor Cell Proliferation in Colorectal Cancer by Inhibition of Smad3-Mediated Tumor Glycolysis." Cell Death and Disease 8.5 (2017): 10. ProQuest. Web. 8 Apr. 2019
Y. Zhao, E. Samal, D. Srivastava. “Serum response factor regulates a muscle-specific microRNA that targets Hand2 during cardiogenesis.”
Nature 436 (2005), pp. 214-220.
Y. Zhao, D. Srivastava. “A developmental view of microRNA function
Trends”. Biochem. Sci. (2007), 10.1016/j.tibs.2007.1002.1006
in press. Published online March 8, 2007

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