RNA-induced silencing complex
The RNA-induced silencing complex, or RISC, is a multiprotein complex that incorporates one strand of a small interfering RNA (siRNA) or microRNA (miRNA). RISC uses the siRNA or miRNA as a template for recognizing complementary mRNA. When it finds a complementary strand, it activates argonaute (a protein within RISC) and cleaves the RNA. This process is important both in gene regulation by microRNAs and in defense against viral infections, which often use double-stranded RNA as an infectious vector.
The RNA endonuclease Dicer plays a role in aiding RISC action by providing the initial RNA material to activate the complex as well as the first RNA substrate molecule. When the Dicer, which has endonuclease activity against dsRNA and pre-miRNAs, cleaves a pre-miRNA stem-loop or a dsRNA, a 20- to 25-base-pair double-stranded RNA fragment is formed with a two-nucleotide 3' overhang at each end.
- One strand is integrated into the RISC complex. This strand is known as the guide strand and is selected by the argonaute protein, the catalytically active RNase in the RISC complex, on the basis of the thermodynamic stability of the 5' end. The strand with a less thermodynamically stable 5' end is loaded into the RISC complex.
- The remaining strand, known as the anti-guide or passenger strand, is degraded as a RISC complex substrate.
The RISC with a bound siRNA recognizes complementary messenger RNA (mRNA) molecules and degrades them, resulting in substantially decreased levels of protein translation and effectively turning off the gene. It is as yet unclear how the activated RISC complex locates the mRNA targets in the cell, though it has been shown that the process can occur in situations outside of ongoing protein translation from mRNA. Endogenously expressed miRNA in metazoans is usually imperfectly complementary to a large number of nuclear genes and has a modulating effect on these genes' levels of expression via translational repression. However, in plants the process has a much greater specificity to the mRNA and usually each miRNA only binds to one mRNA. Recently identified members of RISC complex are SND1(p100 Coactivator or Tudor SN)and AEG-1(MTDH). AEG-1 and SND1 are oncogenes and regulates various gene expression.
- Watson, James D. (2008). Molecular Biology of the Gene. San Francisco, CA: Cold Spring Harbor Laboratory Press. pp. 641–648. ISBN 978-0-8053-9592-1.
- Zamore P, Tuschl T, Sharp P, Bartel D (2000). "RNAi: double-stranded RNA directs the ATP-dependent cleavage of mRNA at 21 to 23 nucleotide intervals". Cell 101 (1): 25–33. doi:10.1016/S0092-8674(00)80620-0. PMID 10778853.
- Vermeulen A, Behlen L, Reynolds A, Wolfson A, Marshall W, Karpilow J, Khvorova A (2005). "The contributions of dsRNA structure to Dicer specificity and efficiency". RNA 11 (5): 674–82. doi:10.1261/rna.7272305. PMC 1370754. PMID 15811921.
- Preall JB, He Z, Gorra JM, Sontheimer EJ (March 2006). "Short interfering RNA strand selection is independent of dsRNA processing polarity during RNAi in Drosophila". Curr. Biol. 16 (5): 530–5. doi:10.1016/j.cub.2006.01.061. PMID 16527750.
- Siomi H, Siomi MC (22 January 2009). "On the road to reading the RNA-interference code". Nature 457 (7228): 396–404. doi:10.1038/nature07754. PMID 19158785.
- Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R (November 2005). "Human RISC couples microRNA biogenesis and posttranscriptional gene silencing". Cell 123 (4): 631–40. doi:10.1016/j.cell.2005.10.022. PMID 16271387.
- Sen GL, Wehrman TS, Blau HM (2005). "mRNA translation is not a prerequisite for small interfering RNA-mediated mRNA cleavage". Differentiation 73 (6): 287–93. doi:10.1111/j.1432-0436.2005.00029.x. PMID 16138829.
- Saumet A, Lecellier CH (2006). "Anti-viral RNA silencing: do we look like plants ?". Retrovirology 3 (3): 3. doi:10.1186/1742-4690-3-3. PMC 1363733. PMID 16409629.
- Yoo BK, Santhekadur PK, Gredler R, Chen D, Emdad L, Bhutia S, Pannell L, Fisher PB, Sarkar D (2011). "Increased RNA-Induced Silencing Complex (RISC) Activity Contributes to Hepatocellular Carcinoma". Hepatology 53 (5): 1538–48. doi:10.1002/hep.24216. PMC 3081619. PMID 21520169.
- Yoo BK, Emdad L, Lee SG, Su ZZ, Santhekadur P, Chen D, Gredler R, Fisher PB, Sarkar D (April 2011). "Astrocyte Elevated Gene-1 (AEG-1): a multifunctional regulator of normal and abnormal physiology". Pharmacol. Ther. 130 (1): 1–8. doi:10.1016/j.pharmthera.2011.01.008. PMC 3043119. PMID 21256156.
- Schwarz DS, Tomari Y, Zamore PD (2004). "The RNA-induced silencing complex is a Mg2+-dependent endonuclease". Curr. Biol. 14 (9): 787–91. doi:10.1016/j.cub.2004.03.008. PMID 15120070.
- Dcr-1 and Dcr-2 have distinct but overlapping roles in the siRNA and miRNA silencing pathways
- RNA-Induced Silencing Complex at the US National Library of Medicine Medical Subject Headings (MeSH)
- RNAiAtlas - database of siRNA libraries and their target analysis results