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- RNA interference is a natural phenomenon by which an mRNA is silenced thereby inhibiting the protein coded from that particular mRNA.
- Scientists have been working on this field from 1990 and finally, two scientists named Andrew Fire and Creg C. Mello shared the Nobel Prize in Physiology or Medicine for their work on RNAi on the nematode worm, Caenorhabditis elegans, which they had published on 1998.
- It has been serving as a very effective tool for the suppression of the desired protein by silencing the required mRNA.
- The basic macro-molecules involved in the RNAi mechanism are two types of RNA molecules: Micro RNA (miRNA) and small interfering RNA (siRNA).
- These two types of RNA can bind to specific mRNA through complementary bonding and inhibit the translation by ribosomes.
- The miRNA are short non-coding RNA nucleotides produced from the chromosome inside the nucleus and have hairpin sequences thereby folding it into double strands.
- The pre-miRNA is bound by a complex of protein called microprocessing unit which contains an RNase III enzyme and a dsRNA binding subunit; this microprocessing unit takes the pre-miRNA from the nucleus to the cytoplasm through the Nuclear pore complex (NPC) where it is subjected to a protein called Dicer, which contains a dsRNA-specific endonuclease subunit, which cleaves some portions of the pre-miRNA and a mature miRNA is produced.
- On the other hand, siRNAs molecules which are exogenous dsRNA nucleotides are similar in sequences to that of miRNA but are not produced inside the nucleus of the cell.
- It comes from external sources. After the processing of miRNA, both miRNA and siRNA contains a passenger strand and a guide strand.
- A complex of protein and RNA called RNA induced silencing complex (RISC) is bound to the guide RNA strand and the passenger RNA strand is degraded.
- This guide strand contains sequences that are complementary to a specific mRNA. It binds to the mRNA and the RISC makes cleavages on the mRNA separating the guide-mRNA double strand.
- The remaining mRNA is degraded by cytosolic exonucleases.
- Hence, the protein coded by the mRNA does not come into existence as the mRNA is silenced.
Image Source: Richard Robinson
A third RNA molecule type, PIWI-interacting RNAs (piRNAs)—the 22–30-nt-long guides for PIWI-clade Argonaute proteins that silence transposons in animal gonads—are generated independently of Dicer from single-stranded precursors. piRNA 5′ ends are defined either by Zucchini, the Drosophila homologue of mitoPLD—a mitochondria-anchored endonuclease. The formation of piRNA’s 3’ end is poorly understood. There can be two genetically and mechanistically distinct pathways for the generation of 3’ end of piRNA in Drosophila. The initiating nucleases are either Zucchini or the PIWI-clade proteins Aubergine (Aub) or Argonaute 3 (Ago 3). While Zucchini-mediated cleavages directly define mature piRNA 3′ ends, Aub/Ago3-mediated cleavages liberate pre-piRNAs that require extensive resection by the 3′-to-5′ exoribonuclease Nibbler (Drosophila homologue of Mut-7). (1, 2)
- Rippei Hayashi, Jakob Schnabl, Dominik Handler, Fabio Mohn, Stefan L. Ameres, Julius Brennecke, Genetic and mechanistic diversity of piRNA 3′-end formation. Nature (2016).
- Han, B. W., Wang, W., Li, C., Weng, Z. & Zamore, P. D. Noncoding RNA. piRNA-guided transposon cleavage initiates Zucchini-dependent, phased piRNA production. Science (2015).
RNA Interference (RNAi)