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Lauren-Koester

Page history last edited by L.Koester 14 years, 11 months ago

 

 

Drosha


 Drosha is a class II RNase III enzyme which plays a key role in microRNA(miRNA) biogenesis in RNA interference by cleaving primary miRNAs(pri-miRNAs) to release hairpin-shaped pre-miRNAs out of the nucleus into the cytoplasm that are then cut by another RNase protein, Dicer, to generate mature miRNAs.(1)

 

 

Contents

I. What mechanism is Drosha involved in?

   A. RNA interference

 

 II. How does Drosha work?

   A. What it does and how it does it.

   B. Drosha needs Pasha/DGCR8

 

III. Structure

   A. Belongs to Ribonuclease III family

IV. Human Diseases Associated with Drosha
   A. Ovarian Cancer


V. Drosha related Therapuetics

 

 

 

 

 

What mechanism is Drosha involved in?


RNA Interference

      

     Drosha plays a role in the mechanism of RNA interference (RNAi).  RNA interference is a safeguard process by which small, interfering RNA molecules specifically induce target mRNA degradation or inhibition of the expression of its target. RNA-interfering molecules, have different roles in this mechanism which act to silence gene expression either by blocking translation or decaying the target mRNA , etc.  More specifically, Drosha is involved in the RNA interference process of miRNA biogenesis.  This process takes place in the nucleus and is responsible for taking pri-miRNA and turning them into pre-miRNA hairpin formations which are then transported out of the nucleus and into the cytoplasm. (2)

 

 

 

 

 

Figure 1. RNA interference 

Image Source: RNA interference in embryonic stem cells.. 

 

 

 Learn more about! SEE VIDEO 1.- RNA interference

 

 

 

 

 

How does Drosha work? 


What it does and How it does it.

          

     The ribonuclease III (RNase III) enzyme Drosha cleaves pri-miRNAs ~70 nucleotide hair pin like structures, called precursor miRNAs (pre-miRNAs).  Pre-miRNAs contain ~22 nucleotide mature miRNA

in 5’ or 3’ half of their stem and cuts which are made by Drosha establish the 5’ or 3’ end of the mature miRNA.  In order to be moved from the nucleus into the cytoplasm pre-miRNAs are moved by the protein Exportin 5, which is able to recognize the 2-3 nucleotide 3’ overhang left over by Drosha at the base of the pre-miRNA stem.  The stem is characteristic of cleavage of RNase III (3),(6).

 

 

Drosha needs Pasha/DGCR8

 

The double stranded RNA binding protein known as Pasha(flies) or DGCR8(mammals) act together with Drosha to alter pri-miRNA to pre-miRNA.  Pasha or DGCR8 binds directly to the central region and RNase III domains on the Drosha protein.  Drosha and Pasha/DGCR8 co-exist as a 500-650 kaDa complex, the microProcessor, which facilitates pri-miRNA conversion.  It is thought that the microprocessor may contain more than one copy of each Drosha or Pasha/DGCR8, or may contain additional proteins (3).

 

 

 

 

 

Structure 


Belongs to Ribonuclease III family

          

      Drosha is a class II RNase III enzyme.  RNase III enzymes cut double-stranded RNA by using Mg2+ to help catalyze.  Drosha, like all RNase III enzymes usually have both RIIIDs and double-stranded binding domains.  Because Drosha belongs to class II it includes two tandem RIIIDs (3).  All RNase III species cloned to date are made of a signature sequence (HNERLEFLGDS) (9.)

 

 

 

 

 

Figure 2. Ribonuclease III family proteins and their double-stranded RNA binding protein partners 

Image Source-RNase proteins and their partners 

 

 

 

 

 

Human Diseases Associated with Drosha


Ovarian Cancer

 

     Levels of two proteins Dicer and Drosha are shown to be strongly associated with a woman's likelihood of survival in ovarian cancer.  A University of Texas study found, that when high levels of Dicer and Drosha are present the median survival rate of women with this cancer was 11 years, and those with low levels of proteins their median survival rate was 2.66 years. (4.),(5.)

 

 

Learn More About! SEE VIDEO 2.- RNA interference proteins tied to cancer survival rates

 

 

 

 

 

 Drosha related Therapeutics


  RNAi based-therapeutics

     

     The mechanism of RNA interference, which involves the protein Drosha, has huge therapuetic potential.  Its promising potential comes from its ability to "silence" genes.  This mechanism gives scientists a huge biological lever to stop genes from producing proteins in the cell.  This is important because many diseases today are caused by over production of proteins in cells (7).  This approach would be particularly useful in targeting genes that encode 'non-druggable' targets that are not willing of conventional therapeutics like small molecules, proteins, or monoclonal antibodies (8).

 

 

 

SEE VIDEO 3- Learn how RNA Interference can be used to find new therapies for human disease. 

 

SEE VIDEO 4- Learn Gene therapy using RNA interference- Cancer 

 

 

 

 

 

 

 

References


(1.) Han, J., Y. Lee, KH Yeom, YK Kim, H. Jin, and VN Kim.The Drosha-DGCR8 complex in primary microRNA      processing.Genes Dev. 18 (2004): 3016-027. NCBI.http://genesdev.cship.org/content/18/24/3016/full.html#ref-     list-

 

(2.) Plourde, Tommy. MicroRNAs: the small RNA revolution. Rep. International Biopharmaceutical Association      Publication. http://www.ibpassociation.org/IBPA_articles/mar2007issue/miRNAs.doc

 

(3.)Tomari, Yukihide, and Phillip Zamore. "MicroRNA Biogenesis: Drosha Can't Cut it without a Partner." Current Biology 15 (2005): R61-64. Science Direct. http://www.sciencedirect.com/.

 

(4.)William, Merritt, comp. "Dicer, Drosha, and Outcomes in patients with ovarian cancer." The New England     Journal of Medicine 359 (2008): 2641-650. Find-Health-Articles.com. www.find-health-articles.com/.

 

(5.)"Weakened RNA interference Reduces Survival in Ovarian Cancer." M.D. Anderson News Release. The      University of Texas MD Anderson Cancer Center. www.mdanderson.org/departments/newsroom/print.cfm.

 

(6)Kuehbacher, Angelika, Carmen Urbich, Andreas Zeiher, and Stefanie Dimmeler. "Role of Dicer and Drosha for Endothelial MicroRNA expression and Angiogenesis." Circulation Research 101 (2007): 59-68. Circulation Research. <circes.ahajournals.org/cgi/content/full/101/1/59>.

 

(7)Berger, Eric. "Houston researchers make ovarian cancer breakthrough." 2008. Houston Chronicle. http://www.chron.com/disp/story.mpl/metropolitan/6169811.html.

 

(8)Soutchek, J. "Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs." Nature 432 (2004): 137-38. http://www.si-rna.com/showabstract.php?pmid=15538359.

 

(9).Wu, H. "Human RNase III is a 160-kDa protein involved in preribosomal RNA processing." J Bio Chem 275 (2000): 36957-6965. NCBI. http://http://www.ncbi.nlm.nih.gov/pubmed/10948199.

Comments (1)

Christopher Korey said

at 8:49 am on Apr 7, 2009

Looks good. As you convert the outline to text, Remember to be concise about each subsection and provide link outs to other pages or papers that provide more in depth detail if that is required. If someone wants more information give them a way to find it not necessarily put it on the page--for example I would describe ovarian cancer and briefly describe how Drosha may be implicated and then link out to abstracts of papers that people could go to if they wanted more information. Try to divide the sections by inserting a horizontal bar. Remember to reference just like any other paper, images as well. I would have only one of the two images since they are redundant--I think the second one may be the better of the two.

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