Drosha
Drosha是一种RNA酶III[5]，在人类基因组中由5号染色体上的DROSHA基因（旧称RNASEN）编码[6][7][8]，于2000年被克隆发表，最初被发现为切割rRNA前驱物（pre-rRNA）的一种RNA酶[9]，现已知其主要功能为在miRNA生成的初期切割miRNA的前驱物，此蛋白可与DGCR8蛋白组成微加工复合体[10]，将DNA转录产生的pri-miRNA切割成长约70nt的pre-miRNA，后者可再由Dicer切割产生成熟的miRNA[11]。Drosha、Dicer与其他参与miRNA生成的蛋白之表现量与某些癌症相关[12]。
功能
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RNA酶III皆为切割双股RNA的RNA内切酶，其中Drosha在细胞核中参与miRNA前驱物切割的初始步骤[8][11]。miRNA的生成过程最初是由RNA聚合酶II转录产生可长达数kb、具5′端帽与多腺苷酸尾的初级转录本pri-miRNA（初级miRNA）[13][14]，其受Drosha切割后会形成长约70nt、且3′端具2个突出碱基（overhang）的pre-miRNA（前miRNA）。pre-miRNA可与XPO5蛋白结合，由细胞核被送入细胞质中，其3′端的突出碱基可被另一种RNA酶IIIDicer所识别，后者可再将pre-miRNA切割成长22nt的双股RNA，其中的一股即是成熟的miRNA，可与RNA诱导沉默复合体（RISC）结合而进行RNA干扰，切割目标mRNA或抑制其翻译以达成基因静默的效果[15]。
Drosha切割pri-miRNA时会与两个RNA结合蛋白DGCR8共同组成称为微加工复合体的蛋白三聚体[16][17][18][19]，DGCR8在模式生物黑腹果蝇与秀丽隐杆线虫中称为Pasha，即“Drosha的伙伴蛋白”（partner of Drosha）之简称[20]，Drosha需在与DGCR8结合的情况下才能进行切割[21]。除必要的Drosha与DGCR8外，微加工复合体还可能包含EWSR1、异质核糖核蛋白、FUS与DEAD-BoxRNA解旋酶（p68、p72）等其他蛋白以帮助切割pri-miRNA[22][23]，有些种类的pri-miRNA只有在特定辅助蛋白存在时才能被Drosha切割[24]。
Drosha大多位于细胞核中，但也有些Drosha不含核定位序列（NLS）而位于细胞质中，称为c-Drosha，可能以其他机制调控基因表达[25][26]。另外Drosha与Dicer也参与DNA修补[27]。
少数miRNA以非典型的方式生成，不需经Drosha切割，此类miRNA称为Mirtron，编码序列位于其他基因的内含子中，可随该基因的mRNA转录后进行剪接时被切割形成pre-miRNA，因此不需依赖Drosha[28]；此外，还有些miRNA（simtron）前驱物的切割仰赖Drosha，但不需DGCR8、XPO5与Dicer[29]。
临床意义
[编辑]Drosha等参与miRNA生成的蛋白表现量与某些癌症相关[12]，例如某些种类的乳癌病患的Drosha与Dicer的表现量下降[30]，癌症基因组图谱中也显示数种乳癌、大肠癌与食管癌病患细胞质中的Drosha（即c-Drosha）表现量增加[25]。
参考文献
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- ^ 1.0 1.1 1.2 GRCh38: Ensembl release 89: ENSG00000113360 - Ensembl, May 2017
- ^ 2.0 2.1 2.2 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
.
- ^ 8.0 8.1 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.
- ^ 11.0 11.1 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.
- ^ 12.0 12.1 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.
- ^ 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.
- ^ 25.0 25.1 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.
