Drosha
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
- ↑ 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.
- ↑ 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.
- 1 2 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.
- 1 2 "Entrez Gene: RNASEN ribonuclease III, nuclear".
- ↑ Fortin KR, Nicholson RH, Nicholson AW (Aug 2002). "Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location". BMC Genomics 3 (1): 26. doi:10.1186/1471-2164-3-26. PMC 122089. PMID 12191433.
- 1 2 3 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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.
- ↑ 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. PMC 1553203. PMID 16882971.
- ↑ 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
- Gunther M, Laithier M, Brison O (Jul 2000). "A set of proteins interacting with transcription factor Sp1 identified in a two-hybrid screening". Molecular and Cellular Biochemistry 210 (1-2): 131–142. doi:10.1023/A:1007177623283. PMID 10976766.
- Fortin KR, Nicholson RH, Nicholson AW (Aug 2002). "Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location". BMC Genomics 3 (1): 26. doi:10.1186/1471-2164-3-26. PMC 122089. PMID 12191433. Check date values in:
|year= / |date= mismatch(help) - 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): 415–419. doi:10.1038/nature01957. PMID 14508493.
- Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (Nov 2004). "The Microprocessor complex mediates the genesis of microRNAs". Nature 432 (7014): 235–240. doi:10.1038/nature03120. PMID 15531877.
- Zeng Y, Yi R, Cullen BR (Jan 2005). "Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha". The EMBO Journal 24 (1): 138–148. doi:10.1038/sj.emboj.7600491. PMC 544904. PMID 15565168.
- Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (Dec 2004). "The Drosha-DGCR8 complex in primary microRNA processing". Genes & Development 18 (24): 3016–3027. doi:10.1101/gad.1262504. PMC 535913. PMID 15574589. Check date values in:
|year= / |date= mismatch(help) - Landthaler M, Yalcin A, Tuschl T (Dec 2004). "The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis". Current Biology : CB 14 (23): 2162–2167. doi:10.1016/j.cub.2004.11.001. PMID 15589161. Check date values in:
|year= / |date= mismatch(help) - Zeng Y, Cullen BR (Jul 2005). "Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences". The Journal of Biological Chemistry 280 (30): 27595–27603. doi:10.1074/jbc.M504714200. PMID 15932881.
- Irvin-Wilson CV, Chaudhuri G (2006). "Alternative initiation and splicing in dicer gene expression in human breast cells". Breast Cancer Research : BCR 7 (4): R563–9. doi:10.1186/bcr1043. PMC 1175071. PMID 15987463.
- Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S (Jan 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research 16 (1): 55–65. doi:10.1101/gr.4039406. PMC 1356129. PMID 16344560.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (Nov 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell 127 (3): 635–648. doi:10.1016/j.cell.2006.09.026. PMID 17081983.
- Sugito N, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Ando T, Mori R, Takashima N, Ogawa R, Fujii Y (Dec 2006). "RNASEN regulates cell proliferation and affects survival in esophageal cancer patients". Clinical Cancer Research : An Official Journal of the American Association for Cancer Research 12 (24): 7322–7328. doi:10.1158/1078-0432.CCR-06-0515. PMID 17121874. Check date values in:
|year= / |date= mismatch(help) - Kim YK, Kim VN (Feb 2007). "Processing of intronic microRNAs". The EMBO Journal 26 (3): 775–783. doi:10.1038/sj.emboj.7601512. PMC 1794378. PMID 17255951.
- Xing L, Kieff E (Sep 2007). "Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication". Journal of Virology 81 (18): 9967–9975. doi:10.1128/JVI.02244-06. PMC 2045418. PMID 17626073.