miRNA-mediated gene silencing by mRNA destabilization

Definition

Target type: biologicalprocess

An RNA interference pathway in which microRNAs (miRNAs) direct the cleavage of target mRNAs. Once incorporated into a RNA-induced silencing complex (RISC), a miRNA base pairing with near-perfect complementarity to the target mRNA will typically direct targeted endonucleolytic cleavage of the mRNA. Many plant miRNAs downregulate gene expression through this mechanism. [GOC:dph, GOC:mtg_lung, PMID:14744438, PMID:15196554, PMID:21118121, PMID:23209154]

MicroRNA (miRNA)-mediated gene silencing by mRNA destabilization is a crucial regulatory mechanism in eukaryotic cells, fine-tuning gene expression and influencing various cellular processes. Here's a detailed description of this process:

1. **miRNA Biogenesis and Processing:** miRNAs are small non-coding RNA molecules typically 21-25 nucleotides long. They are transcribed as primary miRNAs (pri-miRNAs) and undergo a series of processing steps within the nucleus. The pri-miRNAs are cleaved by the Drosha-DGCR8 complex into precursor miRNAs (pre-miRNAs), which are then exported to the cytoplasm. In the cytoplasm, the Dicer enzyme further processes the pre-miRNAs into mature miRNAs, which are then incorporated into the RNA-induced silencing complex (RISC).

2. **Target Recognition and Binding:** Each mature miRNA has a seed sequence, a 6-8 nucleotide region that is complementary to the target mRNA. The RISC complex, containing the mature miRNA, binds to the target mRNA through base pairing between the miRNA seed sequence and the 3' untranslated region (3'UTR) of the mRNA.

3. **mRNA Destabilization:** Once bound to the target mRNA, the RISC complex triggers a cascade of events leading to mRNA destabilization. This typically involves the recruitment of deadenylases, enzymes that remove the poly(A) tail at the 3' end of the mRNA. Deadenylation weakens the mRNA's stability, making it more susceptible to degradation by exonucleases.

4. **Translation Inhibition:** In addition to mRNA destabilization, miRNA-mediated gene silencing can also involve translational repression. The presence of the RISC complex on the target mRNA can block the association of ribosomes with the mRNA, effectively inhibiting translation.

5. **mRNA Degradation:** Following deadenylation and/or translational repression, the target mRNA is ultimately degraded by cellular machinery, such as the exosome complex. This process ensures that the target gene is silenced at the post-transcriptional level.

6. **Specificity and Regulation:** The specificity of miRNA-mediated gene silencing is determined by the complementarity between the miRNA seed sequence and the target mRNA. Different miRNAs can regulate the expression of multiple genes, and a single gene can be targeted by multiple miRNAs. This intricate network of interactions contributes to the fine-tuning of gene expression in response to various cellular signals and environmental stimuli.

In conclusion, miRNA-mediated gene silencing by mRNA destabilization is a complex and highly regulated process that plays a pivotal role in controlling gene expression. By influencing mRNA stability and translation, miRNAs contribute to a diverse range of cellular functions, including development, differentiation, proliferation, apoptosis, and response to stress. This mechanism underscores the importance of post-transcriptional gene regulation in maintaining cellular homeostasis and responding to environmental cues.'
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