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Drosha

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Template:PBB Drosha is a Class 2 ribonuclease III enzyme [1] that in humans is encoded by the DROSHA (formerly RNASEN) gene.[2][3][4]

Function

Members of the ribonuclease III superfamily of double-stranded (ds) RNA-specific endoribonucleases participate in diverse RNA maturation and decay pathways in eukaryotic and prokaryotic cells.[5] The RNase III Drosha is the core nuclease that executes the initiation step of microRNA (miRNA) processing in the nucleus.[4][6]

The microRNAs thus generated are short RNA molecules that regulate a wide variety of other genes by interacting with the RNA-induced silencing complex (RISC) to induce cleavage of complementary messenger RNA (mRNA) as part of the RNA interference pathway. A microRNA molecule is synthesized as a long RNA primary transcript known as a pri-miRNA, which is cleaved by Drosha to produce a characteristic stem-loop structure of about 70 base pairs long, known as a pre-miRNA.[6] Drosha exists as part of a protein complex called the Microprocessor complex, which also contains the double-stranded RNA binding protein Pasha (also called DGCR8).[7] Pasha is essential for Drosha activity and is capable of binding single-stranded fragments of the pri-miRNA that are required for proper processing.[8]

Human Drosha was cloned in 2000, when it was identified as a nuclear dsRNA ribonuclease involved in the processing of ribosomal RNA precursors.[3] The other two human enzymes that participate in the processing and activity of miRNA are the Dicer and Argonaute proteins.

Both Drosha and Pasha are localized to the cell nucleus, where processing of pri-miRNA to pre-miRNA occurs. This latter molecule is then further processed by the RNase Dicer into mature miRNAs in the cell cytoplasm.[6] Both Drosha and Dicer also participate in the DNA damage response.[9]

Clinical significance

Drosha and other miRNA processing enzymes may be important in cancer prognosis.[10] Both Drosha and Dicer can function as master regulators of miRNA processing and have been observed to be down-regulated in some types of breast cancer.[11] However, the nature of the association between microRNA processing and tumorigenesis is unclear.[12]

References

  1. ^ Filippov V, Solovyev V, Filippova M, Gill SS (Mar 2000). "A novel type of RNase III family proteins in eukaryotes". Gene. 245 (1): 213–21. doi:10.1016/s0378-1119(99)00571-5. PMID 10713462.
  2. ^ Filippov V, Solovyev V, Filippova M, Gill SS (Mar 2000). "A novel type of RNase III family proteins in eukaryotes". Gene. 245 (1): 213–221. doi:10.1016/S0378-1119(99)00571-5. PMID 10713462.
  3. ^ a b Wu H, Xu H, Miraglia LJ, Crooke ST (Nov 2000). "Human RNase III is a 160-kDa protein involved in preribosomal RNA processing". The Journal of Biological Chemistry. 275 (47): 36957–36965. doi:10.1074/jbc.M005494200. PMID 10948199.{{cite journal}}: CS1 maint: unflagged free DOI (link) Cite error: The named reference "pmid10948199" was defined multiple times with different content (see the help page).
  4. ^ a b "Entrez Gene: RNASEN ribonuclease III, nuclear".
  5. ^ Fortin KR, Nicholson RH, Nicholson AW (Aug 2002). "Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location". BMC Genomics. 3 (1): 26. PMID 12191433.
  6. ^ a b c Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN (Sep 2003). "The nuclear RNase III Drosha initiates microRNA processing". Nature. 425 (6956): 415–9. doi:10.1038/nature01957. PMID 14508493.
  7. ^ Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ (Nov 2004). "Processing of primary microRNAs by the Microprocessor complex". Nature. 432 (7014): 231–5. doi:10.1038/nature03049. PMID 15531879.
  8. ^ Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN (Jun 2006). "Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex". Cell. 125 (5): 887–901. doi:10.1016/j.cell.2006.03.043. PMID 16751099.
  9. ^ Francia S, Michelini F, Saxena A, Tang D, de Hoon M, Anelli V, Mione M, Carninci P, d'Adda di Fagagna F (Aug 2012). "Site-specific DICER and DROSHA RNA products control the DNA-damage response". Nature. 488 (7410): 231–5. doi:10.1038/nature11179. PMID 22722852.
  10. ^ Slack FJ, Weidhaas JB (Dec 2008). "MicroRNA in cancer prognosis". The New England Journal of Medicine. 359 (25): 2720–2. doi:10.1056/NEJMe0808667. PMID 19092157.
  11. ^ Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (Aug 2006). "Extensive post-transcriptional regulation of microRNAs and its implications for cancer". Genes & Development. 20 (16): 2202–7. doi:10.1101/gad.1444406. PMID 16882971.
  12. ^ Iorio MV, Croce CM (Jun 2012). "microRNA involvement in human cancer". Carcinogenesis. 33 (6): 1126–33. doi:10.1093/carcin/bgs140. PMID 22491715.

Further reading

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