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[[File:MiRNA processing.svg|thumb|MiRNA processing]]
[[File:MiRNA processing.svg|thumb|MiRNA processing]]

==General Overview==

RNA silencing describes several mechanistically related pathways which are involved in controlling and regulating gene expression.<ref>{{cite journal|last=Moazed|first=D|title=Small RNAs in transcriptional gene silencing and genome defence.|journal=Nature|date=2009 Jan 22|volume=457|issue=7228|pages=413-20|pmid=19158787}}</ref><ref>{{cite journal|last=Pickford|first=AS|coauthors=Cogoni, C|title=RNA-mediated gene silencing.|journal=Cellular and molecular life sciences : CMLS|date=2003 May|volume=60|issue=5|pages=871-82|pmid=12827277}}</ref><ref>{{cite journal|last=Tijsterman|first=M|coauthors=Ketting, RF; Plasterk, RH|title=The genetics of RNA silencing.|journal=Annual review of genetics|date=2002|volume=36|pages=489-519|pmid=12429701}}</ref> RNA silencing pathways are associated with the regulatory activity of small non-coding RNAs (approximately 20–30 nucleotides in length) that function as factors involved in inactivating homologous sequences, promoting endonuclease activity, translational arrest, and/or chromatic or DNA modification.<ref>{{cite journal|last=Malecová|first=B|coauthors=Morris, KV|title=Transcriptional gene silencing through epigenetic changes mediated by non-coding RNAs.|journal=Current opinion in molecular therapeutics|date=2010 Apr|volume=12|issue=2|pages=214-22|pmid=20373265}}</ref><ref>{{cite journal|last=MEISTER|first=G.|title=Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing|journal=RNA|date=1 March 2004|volume=10|issue=3|pages=544–550|doi=10.1261/rna.5235104}}</ref><ref>{{cite journal|last=Zhou|first=H|coauthors=Hu, H; Lai, M|title=Non-coding RNAs and their epigenetic regulatory mechanisms.|journal=Biology of the cell / under the auspices of the European Cell Biology Organization|date=2010 Dec|volume=102|issue=12|pages=645-55|pmid=21077844}}</ref>

RNA has been largely investigated within its role as an intermediary in the translation of genes into proteins.<ref>{{cite journal|last=Eccleston|first=Alex|coauthors=Angela K. Eggleston|title=RNA Interference|journal=Nature|year=2004|volume=431|issue=7006|pages=338|url=http://www.nature.com/nature/insights/7006.html}}</ref> These more active regulatory functions, however, only began to be addressed by researchers beginning in the late-1990s.<ref>{{cite journal|last=Eggleston|first=Angela K.|title=RNA silencing|journal=Nature|date=22 January 2009|year=2009|volume=457|issue=7228|pages=395–395|doi=10.1038/457395a}}</ref> The landmark study providing an understanding of the first identified mechanism was published in 1998 by Fire et al.,<ref>{{cite journal|last=Fire|first=A|coauthors=Xu, S; Montgomery, MK; Kostas, SA; Driver, SE; Mello, CC|title=Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans.|journal=Nature|date=1998 Feb 19|volume=391|issue=6669|pages=806-11|pmid=9486653}}</ref> demonstrating that double-stranded RNA could act as a trigger for gene silencing.<ref>{{cite journal|last=Eggleston|first=Angela K.|title=RNA silencing|journal=Nature|date=22 January 2009|volume=457|issue=7228|pages=395–395|doi=10.1038/457395a}}</ref> Since then, various other classes of RNA silencing have been identified and characterized.<ref>{{cite journal|last=Moazed|first=D|title=Small RNAs in transcriptional gene silencing and genome defence.|journal=Nature|date=2009 Jan 22|volume=457|issue=7228|pages=413-20|pmid=19158787}}</ref> Presently, the therapeutic potential of these discoveries is being explored, for example, in the context of targeted gene therapy.<ref>{{cite journal|last=Takeshita|first=F|coauthors=Ochiya, T|title=Therapeutic potential of RNA interference against cancer.|journal=Cancer science|date=2006 Aug|volume=97|issue=8|pages=689-96|pmid=16863503}}</ref><ref>{{cite journal|last=Dykxhoorn|first=DM|coauthors=Novina, CD; Sharp, PA|title=Killing the messenger: short RNAs that silence gene expression.|journal=Nature reviews. Molecular cell biology|date=2003 Jun|volume=4|issue=6|pages=457-67|pmid=12778125}}</ref>

While RNA silencing is an evolving class of mechanisms, a common theme is the fundamental relationship between small RNAs and gene expression.<ref>{{cite journal|last=MEISTER|first=G.|title=Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing|journal=RNA|date=1 March 2004|volume=10|issue=3|pages=544–550|doi=10.1261/rna.5235104}}</ref> It has also been observed that the major RNA silencing pathways currently identified have mechanisms of action which may involve both post-transcriptional gene silencing (PTGS)<ref>{{cite journal|last=Hammond|first=SM|coauthors=Caudy, AA; Hannon, GJ|title=Post-transcriptional gene silencing by double-stranded RNA.|journal=Nature reviews. Genetics|date=2001 Feb|volume=2|issue=2|pages=110-9|pmid=11253050}}</ref>—also referred to as RNA interference or [[RNA_interference|iRNA]]—as well as chromatin-dependent gene silencing (CDGS) pathways.<ref>{{cite journal|last=Moazed|first=D|title=Small RNAs in transcriptional gene silencing and genome defence.|journal=Nature|date=2009 Jan 22|volume=457|issue=7228|pages=413-20|pmid=19158787}}</ref> CDGS involves the assembly of small RNA complexes on nascent transcripts and is regarded as encompassing mechanisms of action which implicate transcriptional gene silencing (TGS) and co-transcriptional gene silencing (CTGS) events.<ref>{{cite journal|last=Bühler|first=M|title=RNA turnover and chromatin-dependent gene silencing.|journal=Chromosoma|date=2009 Apr|volume=118|issue=2|pages=141-51|pmid=19023586}}</ref> This is significant at least because the evidence suggests that small RNAs play a role in the modulation of chromatin structure and TGS.<ref>{{cite journal|last=Gonzalez|first=S|coauthors=Pisano, DG; Serrano, M|title=Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs.|journal=Cell cycle (Georgetown, Tex.)|date=2008 Aug 15|volume=7|issue=16|pages=2601-8|pmid=18719372}}</ref><ref>{{cite journal|last=Kim|first=JK|coauthors=Gabel, HW; Kamath, RS; Tewari, M; Pasquinelli, A; Rual, JF; Kennedy, S; Dybbs, M; Bertin, N; Kaplan, JM; Vidal, M; Ruvkun, G|title=Functional genomic analysis of RNA interference in C. elegans.|journal=Science (New York, N.Y.)|date=2005 May 20|volume=308|issue=5725|pages=1164-7|pmid=15790806}}</ref>


==RNA Silencing Mechanisms==
==RNA Silencing Mechanisms==

Revision as of 16:44, 5 April 2013

RNA silencing (also called as post-transcriptional gene silencing PTGS) refers to a family of gene silencing effects by which the expression of one or more genes is downregulated or entirely suppressed by the introduction of an antisense RNA molecule. The most common and well-studied example is RNA interference, in which endogenously expressed microRNA or exogenously derived small interfering RNA induces the degradation of complementary messenger RNA. It also plays an important role in defending plants against viruses. Enzymes detect double stranded RNA (that is not normally found in cells) and digest it into small pieces that are not able to cause disease.[1][2][3][4][5]

MiRNA processing

General Overview

RNA silencing describes several mechanistically related pathways which are involved in controlling and regulating gene expression.[6][7][8] RNA silencing pathways are associated with the regulatory activity of small non-coding RNAs (approximately 20–30 nucleotides in length) that function as factors involved in inactivating homologous sequences, promoting endonuclease activity, translational arrest, and/or chromatic or DNA modification.[9][10][11]

RNA has been largely investigated within its role as an intermediary in the translation of genes into proteins.[12] These more active regulatory functions, however, only began to be addressed by researchers beginning in the late-1990s.[13] The landmark study providing an understanding of the first identified mechanism was published in 1998 by Fire et al.,[14] demonstrating that double-stranded RNA could act as a trigger for gene silencing.[15] Since then, various other classes of RNA silencing have been identified and characterized.[16] Presently, the therapeutic potential of these discoveries is being explored, for example, in the context of targeted gene therapy.[17][18]

While RNA silencing is an evolving class of mechanisms, a common theme is the fundamental relationship between small RNAs and gene expression.[19] It has also been observed that the major RNA silencing pathways currently identified have mechanisms of action which may involve both post-transcriptional gene silencing (PTGS)[20]—also referred to as RNA interference or iRNA—as well as chromatin-dependent gene silencing (CDGS) pathways.[21] CDGS involves the assembly of small RNA complexes on nascent transcripts and is regarded as encompassing mechanisms of action which implicate transcriptional gene silencing (TGS) and co-transcriptional gene silencing (CTGS) events.[22] This is significant at least because the evidence suggests that small RNAs play a role in the modulation of chromatin structure and TGS.[23][24]

RNA Silencing Mechanisms

The most basic mechanistic flow for RNA Silencing is as follows:

1: RNA with inverted repeats hairpin/panhandle constructs --> 2: dsRNA --> 3: miRNAs/siRNAs --> 4: RISC --> 5: Destruction of target mRNA

  1. It has been discovered that the best precursor to good RNA silencing is to have single stranded antisense RNA with inverted repeats, which in turn build small hairpin RNA and panhandle constructs. [25] The hairpin or panhandle constructs exist so that the RNA can remain independent and not anneal with other RNA strands.
  2. These small hairpin RNAs and/or panhandles then get transported from the nucleus to the cytosol through the nuclear export receptor called exportin-5, and then get transformed into a dsRNA, a double stranded RNA, which, like DNA, is a double stranded series of nucleotides. If a dsRNA were only built with a single strand, there would be a higher chance for it to anneal to other "good" mRNAs. As a double strand, it can be kept on call for when it is needed.
  3. The dsRNA then gets cut up by a Dicer into small (21-28 nt = nucleotides long) strands of miRNAs (microRNAs) or siRNAs (short interfering RNAs.) A Dicer is an endoribonuclease RNase, which is a complex of a protein mixed with strand(s) of RNA.
  4. Lastly, the double stranded miRNAs/siRNAs separate into single strands; the antisense RNA strand of the two will combine with another endoribonuclease enzyme complex called RISC (RNA-induced silencing complex) and will guide the RISC to break up the "perfectly complementary" target mRNA or viral genomic RNA so that it can be destroyed. [5][25]
  5. It means that based on a short sequence specific area, a corresponding mRNA will be cut. To make sure, it will be cut in many other places as well. (If the mechanism only worked with a long stretch, then there would be higher chance that it would not have time to match to its complementary long mRNA.) (Question: why aren't many different "good" mRNAs cut at the same time?) It has also been shown that the repeated-associated short interference RNAs (rasiRNA) have a role in guiding chromatin modification. [5] (p. 364)

See also

References

  1. ^ Ding SW (2000). "RNA silencing". Curr Opin Biotechnol. 11 (2): 152–6. PMID 10753772.
  2. ^ Susi P, Hohkuri M, Wahlroos T, Kilby NJ (2004). "Characteristics of RNA silencing in plants: similarities and differences across kingdoms". Plant Mol Biol. 54 (2): 157–74. PMID 15159620.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ Baulcombe D (2004). "RNA silencing in plants". Nature. 431 (7006): 356–63. doi:10.1038/nature02874. PMID 15372043.
  4. ^ Baulcombe D (2005). "RNA silencing". Trends Biochem Sci. 30 (6): 290–3. doi:10.1016/j.tibs.2005.04.012. PMID 15950871.
  5. ^ a b c Meister, G.; Tuschl, T. (2004), "[PDF] from blatny.com" (PDF), Nature, 431 (7006): 343–349, retrieved 2011-02-08
  6. ^ Moazed, D (2009 Jan 22). "Small RNAs in transcriptional gene silencing and genome defence". Nature. 457 (7228): 413–20. PMID 19158787. {{cite journal}}: Check date values in: |date= (help)
  7. ^ Pickford, AS (2003 May). "RNA-mediated gene silencing". Cellular and molecular life sciences : CMLS. 60 (5): 871–82. PMID 12827277. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  8. ^ Tijsterman, M (2002). "The genetics of RNA silencing". Annual review of genetics. 36: 489–519. PMID 12429701. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  9. ^ Malecová, B (2010 Apr). "Transcriptional gene silencing through epigenetic changes mediated by non-coding RNAs". Current opinion in molecular therapeutics. 12 (2): 214–22. PMID 20373265. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  10. ^ MEISTER, G. (1 March 2004). "Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing". RNA. 10 (3): 544–550. doi:10.1261/rna.5235104.
  11. ^ Zhou, H (2010 Dec). "Non-coding RNAs and their epigenetic regulatory mechanisms". Biology of the cell / under the auspices of the European Cell Biology Organization. 102 (12): 645–55. PMID 21077844. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  12. ^ Eccleston, Alex (2004). "RNA Interference". Nature. 431 (7006): 338. {{cite journal}}: Unknown parameter |coauthors= ignored (|author= suggested) (help)
  13. ^ Eggleston, Angela K. (22 January 2009). "RNA silencing". Nature. 457 (7228): 395–395. doi:10.1038/457395a.{{cite journal}}: CS1 maint: date and year (link)
  14. ^ Fire, A (1998 Feb 19). "Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans". Nature. 391 (6669): 806–11. PMID 9486653. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  15. ^ Eggleston, Angela K. (22 January 2009). "RNA silencing". Nature. 457 (7228): 395–395. doi:10.1038/457395a.
  16. ^ Moazed, D (2009 Jan 22). "Small RNAs in transcriptional gene silencing and genome defence". Nature. 457 (7228): 413–20. PMID 19158787. {{cite journal}}: Check date values in: |date= (help)
  17. ^ Takeshita, F (2006 Aug). "Therapeutic potential of RNA interference against cancer". Cancer science. 97 (8): 689–96. PMID 16863503. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  18. ^ Dykxhoorn, DM (2003 Jun). "Killing the messenger: short RNAs that silence gene expression". Nature reviews. Molecular cell biology. 4 (6): 457–67. PMID 12778125. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  19. ^ MEISTER, G. (1 March 2004). "Sequence-specific inhibition of microRNA- and siRNA-induced RNA silencing". RNA. 10 (3): 544–550. doi:10.1261/rna.5235104.
  20. ^ Hammond, SM (2001 Feb). "Post-transcriptional gene silencing by double-stranded RNA". Nature reviews. Genetics. 2 (2): 110–9. PMID 11253050. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  21. ^ Moazed, D (2009 Jan 22). "Small RNAs in transcriptional gene silencing and genome defence". Nature. 457 (7228): 413–20. PMID 19158787. {{cite journal}}: Check date values in: |date= (help)
  22. ^ Bühler, M (2009 Apr). "RNA turnover and chromatin-dependent gene silencing". Chromosoma. 118 (2): 141–51. PMID 19023586. {{cite journal}}: Check date values in: |date= (help)
  23. ^ Gonzalez, S (2008 Aug 15). "Mechanistic principles of chromatin remodeling guided by siRNAs and miRNAs". Cell cycle (Georgetown, Tex.). 7 (16): 2601–8. PMID 18719372. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  24. ^ Kim, JK (2005 May 20). "Functional genomic analysis of RNA interference in C. elegans". Science (New York, N.Y.). 308 (5725): 1164–7. PMID 15790806. {{cite journal}}: Check date values in: |date= (help); Unknown parameter |coauthors= ignored (|author= suggested) (help)
  25. ^ a b Tijsterman M, Ketting RF, Plasterk RH (2002). "The genetics of RNA silencing". Annu. Rev. Genet. 36: 489–519. doi:10.1146/annurev.genet.36.043002.091619. PMID 12429701.{{cite journal}}: CS1 maint: multiple names: authors list (link)


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