RNA-induced silencing complex

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RNA-induced silencing complex, or RISC, is a multi-protein siRNA complex which cleaves (incoming viral) dsRNA and binds short antisense RNA strands which are then able to bind complementary strands. When it finds the complementary strand, it activates RNAse activity and cleaves the RNA. This process is important both in gene regulation by micro-RNAs and in defense against viral infections, which often use double-stranded RNA as an infectious vector.

Strands

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 Dicer, which has endonuclease activity against dsRNA and pre-miRNAs, cleaves a pre-miRNA stem-loop or a dsRNA, a 20-25 base pair double-stranded RNA fragment is formed with a 2 nucleotide 3' overhang at each end.[1][2]

  • 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 stability of the 5' end.[3]
  • The remaining strand, known as the anti-guide or passenger strand, is degraded as a RISC complex substrate.[4]

Binding

The RISC complex 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 is not coupled to ongoing protein translation from the mRNA.[5] Endogenously expressed miRNA 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.[6]

References

  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. PMID 10778853.
  2. 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. PMID 15811921.
  3. Preall JB, He Z, Gorra JM, Sontheimer EJ. (2006). The single strand of RNA for which the 5' end is at the less stably base paired end of the double stranded siRNA is preferred for selection as the guide. Short interfering RNA strand selection is independent of dsRNA processing polarity during RNAi in Drosophila. Curr Biol 16(5):530-5.
  4. Gregory RI, Chendrimada TP, Cooch N, Shiekhattar R. (2005). Human RISC couples microRNA biogenesis and posttranscriptional gene silencing. Cell 123(4):631-40.
  5. 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.
  6. Saumet A, Lecellier CH (2006). "Anti-viral RNA silencing: do we look like plants?". Retrovirology. 3 (3). PMID 16409629.

External links

  • 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.

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