Drosha

Drosha是一種RNA酶III，在人類基因組中由5號染色體上的DROSHA基因（舊稱RNASEN）編碼，於2000年被克隆發表，最初被發現為切割rRNA前驅物（pre-rRNA）的一種RNA酶，現已知其主要功能為在miRNA生成的初期切割miRNA的前驅物，此蛋白可與DGCR8蛋白組成微加工复合体（英语：Microprocessor complex），將DNA轉錄產生的pri-miRNA切割成長約70nt的pre-miRNA，後者可再由Dicer切割產生成熟的miRNA。Drosha、Dicer與其他參與miRNA生成的蛋白之表現量與某些癌症相關。 RNA酶III皆為切割雙股RNA的RNA內切酶，其中Drosha在細胞核中參與miRNA前驅物切割的初始步驟。miRNA的生成過程最初是由RNA聚合酶II轉錄產生可長達數kb、具5′端帽與多腺苷酸尾的初級轉錄本（英语：primary transcript）pri-miRNA（初級miRNA），其受Drosha切割後會形成長約70nt、且3′端具2個突出鹼基（overhang）的pre-miRNA（前miRNA）。pre-miRNA可與XPO5（英语：XPO5）蛋白結合，由細胞核被送入細胞質中，其3′端的突出鹼基可被另一種RNA酶IIIDicer所識別，後者可再將pre-miRNA切割成長22nt的雙股RNA，其中的一股即是成熟的miRNA，可與RNA誘導沉默複合體（RISC）結合而進行RNA干擾，切割目標mRNA或抑制其轉譯以達成基因靜默的效果。 Drosha切割pri-miRNA時會與兩個RNA結合蛋白DGCR8共同組成稱為微加工复合体（英语：Microprocessor complex）的蛋白三聚體，DGCR8在模式生物黑腹果蠅與秀麗隱桿線蟲中稱為Pasha，即「Drosha的夥伴蛋白」（partner of Drosha）之簡稱，Drosha需在與DGCR8結合的情況下才能進行切割。除必要的Drosha與DGCR8外，微加工复合体還可能包含EWSR1（英语：EWSR1）、异质核糖核蛋白（英语：Heterogeneous ribonucleoprotein particle）、FUS與DEAD-BoxRNA解旋酶（p68（英语：DDX5）、p72（英语：DDX17））等其他蛋白以幫助切割pri-miRNA，有些種類的pri-miRNA只有在特定輔助蛋白存在時才能被Drosha切割。 Drosha大多位於細胞核中，但也有些Drosha不含核定位序列（NLS）而位於細胞質中，稱為c-Drosha，可能以其他機制調控基因表現。另外Drosha與Dicer也參與DNA修補。 少數miRNA以非典型的方式生成，不需經Drosha切割，此類miRNA稱為Mirtron（英语：Mirtron），編碼序列位於其他基因的內含子中，可隨該基因的mRNA轉錄後進行剪接時被切割形成pre-miRNA，因此不需依賴Drosha；此外，還有些miRNA（simtron）前驅物的切割仰賴Drosha，但不需DGCR8、XPO5與Dicer。 Drosha等參與miRNA生成的蛋白表現量與某些癌症相關，例如某些種類的乳癌病患的Drosha與Dicer的表現量下降，癌症基因組圖譜中也顯示數種乳癌、大腸癌與食道癌病患細胞質中的Drosha（即c-Drosha）表現量增加。 分子与细胞生物学主题 GRCh38: Ensembl release 89: ENSG00000113360 - Ensembl, May 2017 GRCm38: Ensembl release 89: ENSMUSG00000022191 - Ensembl, May 2017 Human PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.  Mouse PubMed Reference:. National Center for Biotechnology Information, U.S. National Library of Medicine.  Filippov V, Solovyev V, Filippova M, Gill SS. A novel type of RNase III family proteins in eukaryotes. Gene. 2000, 245 (1): 213–21. PMID 10713462. doi:10.1016/s0378-1119(99)00571-5.  Filippov V, Solovyev V, Filippova M, Gill SS. A novel type of RNase III family proteins in eukaryotes. Gene. 2000, 245 (1): 213–21. PMID 10713462. doi:10.1016/S0378-1119(99)00571-5.  Wu H, Xu H, Miraglia LJ, Crooke ST. Human RNase III is a 160-kDa protein involved in preribosomal RNA processing. The Journal of Biological Chemistry. 2000, 275 (47): 36957–65. PMID 10948199. doi:10.1074/jbc.M005494200 .  Entrez Gene: RNASEN ribonuclease III, nuclear.  Wu H, Xu H, Miraglia LJ, Crooke ST. Human RNase III is a 160-kDa protein involved in preribosomal RNA processing.. J Biol Chem. 2000, 275 (47): 36957–65. PMID 10948199. doi:10.1074/jbc.M005494200.  Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004, 432 (7014): 231–5. PMID 15531879. S2CID 4425505. doi:10.1038/nature03049.  Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN. The nuclear RNase III Drosha initiates microRNA processing. Nature. 2003, 425 (6956): 415–9. PMID 14508493. S2CID 4421030. doi:10.1038/nature01957.  Slack FJ, Weidhaas JB. MicroRNA in cancer prognosis.. N Engl J Med. 2008, 359 (25): 2720–2. PMID 19092157. doi:10.1056/NEJMe0808667.  Conrad T, Ntini E, Lang B, Cozzuto L, Andersen JB, Marquardt JU; et al. Determination of primary microRNA processing in clinical samples by targeted pri-miR-sequencing.. RNA. 2020, 26 (11): 1726–1730. PMC 7566579 . PMID 32669295. doi:10.1261/rna.076240.120.  Cai X, Hagedorn CH, Cullen BR. Human microRNAs are processed from capped, polyadenylated transcripts that can also function as mRNAs.. RNA. 2004, 10 (12): 1957–66. PMC 1370684 . PMID 15525708. doi:10.1261/rna.7135204.  Saito K, Ishizuka A, Siomi H, Siomi MC. Processing of pre-microRNAs by the Dicer-1-Loquacious complex in Drosophila cells.. PLoS Biol. 2005, 3 (7): e235. PMC 1141268 . PMID 15918769. doi:10.1371/journal.pbio.0030235.  Partin, Alexander C.; Zhang, Kaiming; Jeong, Byung-Cheon; Herrell, Emily; Li, Shanshan; Chiu, Wah; Nam, Yunsun. Cryo-EM Structures of Human Drosha and DGCR8 in Complex with Primary MicroRNA. Molecular Cell. 2020, 78 (3): 411–422.e4. PMC 7214211 . PMID 32220646. doi:10.1016/j.molcel.2020.02.016.  Kwon SC, Nguyen TA, Choi YG, Jo MH, Hohng S, Kim VN, Woo JS. Structure of Human DROSHA. Cell. 2016, 164 (1–2): 81–90. PMID 26748718. doi:10.1016/j.cell.2015.12.019 .  Herbert KM, Sarkar SK, Mills M, Delgado De la Herran HC, Neuman KC, Steitz JA. A heterotrimer model of the complete Microprocessor complex revealed by single-molecule subunit counting. RNA. 26683315, 22 (2): 175–83. PMC 4712668 . doi:10.1261/rna.054684.115.  请检查|date=中的日期值 (帮助) Nguyen TA, Jo MH, Choi YG, Park J, Kwon SC, Hohng S, et al. Functional Anatomy of the Human Microprocessor. Cell. 2015, 161 (6): 1374–87. PMID 26027739. doi:10.1016/j.cell.2015.05.010 .  Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ. Processing of primary microRNAs by the Microprocessor complex. Nature. 2004, 432 (7014): 231–5. PMID 15531879. doi:10.1038/nature03049.  Han J, Lee Y, Yeom KH, Nam JW, Heo I, Rhee JK, Sohn SY, Cho Y, Zhang BT, Kim VN. Molecular basis for the recognition of primary microRNAs by the Drosha-DGCR8 complex. Cell. 2006, 125 (5): 887–901. PMID 16751099. S2CID 453021. doi:10.1016/j.cell.2006.03.043 .  Siomi H, Siomi MC. Posttranscriptional regulation of microRNA biogenesis in animals. Molecular Cell. 2010, 38 (3): 323–32. PMID 20471939. doi:10.1016/j.molcel.2010.03.013 .  Suzuki HI, Miyazono K. Emerging complexity of microRNA generation cascades.. J Biochem. 2011, 149 (1): 15–25. PMID 20876186. doi:10.1093/jb/mvq113.  Ha M, Kim VN. Regulation of microRNA biogenesis. Nature Reviews. Molecular Cell Biology. 2014, 15 (8): 509–24. PMID 25027649. S2CID 205495632. doi:10.1038/nrm3838.  Dai L, Chen K, Youngren B, Kulina J, Yang A, Guo Z; et al. Cytoplasmic Drosha activity generated by alternative splicing.. Nucleic Acids Res. 2016, 44 (21): 10454–10466. PMC 5137420 . PMID 27471035. doi:10.1093/nar/gkw668.  Link S, Grund SE, Diederichs S. Alternative splicing affects the subcellular localization of Drosha. Nucleic Acids Research. 2016, 44 (11): 5330–43. PMC 4914122 . PMID 27185895. doi:10.1093/nar/gk400.  Francia S, Michelini F, Saxena A, Tang D, de Hoon M, Anelli V, Mione M, Carninci P, d'Adda di Fagagna F. Site-specific DICER and DROSHA RNA products control the DNA-damage response. Nature. 2012, 488 (7410): 231–5. PMC 3442236 . PMID 22722852. doi:10.1038/nature11179.  Ruby, JG; Jan, CH; Bartel, DP. Intronic microRNA precursors that bypass Drosha processing. Nature. 2007, 448 (7149): 83–6. Bibcode:2007Natur.448...83R. PMC 2475599 . PMID 17589500. doi:10.1038/nature05983.  Havens MA, Reich AA, Duelli DM, Hastings ML. Biogenesis of mammalian microRNAs by a non-canonical processing pathway.. Nucleic Acids Res. 2012, 40 (10): 4626–40. PMC 3378869 . PMID 22270084. doi:10.1093/nar/gks026.  Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM. Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes & Development. 2006, 20 (16): 2202–7. PMC 1553203 . PMID 16882971. doi:10.1101/gad.1444406.  PDB中UniProt可用的所有結構信息之概述：Q9NRR4 (Ribonuclease 3) 在PDBe-KB（英语：PDBe-KB）。