Drosha
Drosha is a Class 2 ribonuclease III enzyme[5] that in humans is encoded by the DROSHA (formerly RNASEN) gene.[6][7][8] It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and in correlation with Dicer. It has been found significant in clinical knowledge for cancer prognosis[9] and HIV-1 replication.[10]
History
Human Drosha was cloned in 2000 when it was identified as a nuclear dsRNA ribonuclease involved in the processing of ribosomal RNA precursors.[11] The other two human enzymes that participate in the processing and activity of miRNA are the Dicer and Argonaute proteins. Recently, proteins like Drosha have been found significant in cancer prognosis[9] and HIV-1 replication.[10]
Function
Members of the ribonuclease III superfamily of
The microRNAs thus generated are short
Both Drosha and DGCR8 are localized to the cell nucleus, where processing of pri-miRNA to pre-miRNA occurs. These two proteins homeostatically control miRNA biogenesis by an auto-feedback loop.[16] A 2nt 3' overhang is generated by Drosha in the nucleus recognized by Dicer in the cytoplasm, which couples the upstream and downstream processing events. Pre-miRNA is then further processed by the RNase Dicer into mature miRNAs in the cell cytoplasm.[11][16] There also exists an isoform of Drosha that does not contain a nuclear localization signal, which results in the generation of c-Drosha.[17][18] This variant has been shown to localize to the cell cytoplasm rather than the nucleus, but the effects on pri-miRNA processing are yet unclear.
Both Drosha and Dicer also participate in the DNA damage response.[19]
Certain miRNAs have been found to deviate from conventional biogenesis pathways and do not necessarily require Drosha or Dicer, which is because they do not require the processing of pri-miRNA to pre-miRNA.[16] Drosha-independent miRNAs derive from mirtrons, which are genes that encode for miRNAs in their introns and make use of splicing to bypass Drosha cleavage. Simtrons are mirtron-like, splicing-independent, and do require Drosha mediated cleavage, although they do not require most proteins in the canonical pathway such as DGCR8 or Dicer.[10]
Clinical significance
Drosha and other miRNA processing enzymes may be important in cancer prognosis.
Drosha and other miRNA processing enzymes may also be important in HIV-1 replication. miRNAs contribute to the innate antiviral defense. This can be shown by the knockdown of two important miRNA processing proteins, Drosha and Dicer, which leads to a significant enhancement of viral replication in PBMCs from HIV-1-infected patients. Thus, Drosha, in conjunction with Dicer, seem to have a role in controlling HIV-1 replication.[10]
References
- ^ a b c GRCh38: Ensembl release 89: ENSG00000113360 – Ensembl, May 2017
- ^ a b c 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.
- PMID 10713462.
- PMID 10713462.
- PMID 10948199.
- ^ a b "Entrez Gene: RNASEN ribonuclease III, nuclear".
- ^ a b Slack FJ, Weidhaas JB (December 2008). "MicroRNA in cancer prognosis". The New England Journal of Medicine. 359 (25): 2720-2.
- ^ a b c d Swaminathan, G., Navas-Martín, S., & Martín-García, J. (2014). MicroRNAs and HIV-1 infection: antiviral activities and beyond. Journal of molecular biology, 426(6), 1178-1197.
- ^ S2CID 4421030.
- PMID 12191433.
- ^ Sloan, K. E., Gleizes, P. E., & Bohnsack, M. T. (2016). Nucleocytoplasmic transport of RNAs and RNA–protein complexes. Journal of molecular biology, 428(10), 2040-2059.
- S2CID 4425505.
- S2CID 453021.
- ^ a b c d Suzuki, H. I., & Miyazono, K. (2011). Emerging complexity of microRNA generation cascades. The Journal of Biochemistry, 149(1), 15-25.
- PMID 27185895.
- ^ PMID 27471035.
- PMID 22722852.
- PMID 19092157.
- PMID 16882971.
- PMID 22491715.
- PMID 27673562.
Further reading
- Gunther M, Laithier M, Brison O (July 2000). "A set of proteins interacting with transcription factor Sp1 identified in a two-hybrid screening". Molecular and Cellular Biochemistry. 210 (1–2): 131–42. S2CID 1339642.
- Fortin KR, Nicholson RH, Nicholson AW (August 2002). "Mouse ribonuclease III. cDNA structure, expression analysis, and chromosomal location". BMC Genomics. 3 (1): 26. PMID 12191433.
- Lee Y, Ahn C, Han J, Choi H, Kim J, Yim J, Lee J, Provost P, Rådmark O, Kim S, Kim VN (September 2003). "The nuclear RNase III Drosha initiates microRNA processing". Nature. 425 (6956): 415–9. S2CID 4421030.
- Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (November 2004). "The Microprocessor complex mediates the genesis of microRNAs". Nature. 432 (7014): 235–40. S2CID 4389261.
- Zeng Y, Yi R, Cullen BR (January 2005). "Recognition and cleavage of primary microRNA precursors by the nuclear processing enzyme Drosha". The EMBO Journal. 24 (1): 138–48. PMID 15565168.
- Han J, Lee Y, Yeom KH, Kim YK, Jin H, Kim VN (December 2004). "The Drosha-DGCR8 complex in primary microRNA processing". Genes & Development. 18 (24): 3016–27. PMID 15574589.
- Landthaler M, Yalcin A, Tuschl T (December 2004). "The human DiGeorge syndrome critical region gene 8 and Its D. melanogaster homolog are required for miRNA biogenesis". Current Biology. 14 (23): 2162–7. S2CID 13266269.
- Zeng Y, Cullen BR (July 2005). "Efficient processing of primary microRNA hairpins by Drosha requires flanking nonstructured RNA sequences". The Journal of Biological Chemistry. 280 (30): 27595–603. PMID 15932881.
- Irvin-Wilson CV, Chaudhuri G (2006). "Alternative initiation and splicing in dicer gene expression in human breast cells". Breast Cancer Research. 7 (4): R563–9. 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 (January 2006). "Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes". Genome Research. 16 (1): 55–65. PMID 16344560.
- Olsen JV, Blagoev B, Gnad F, Macek B, Kumar C, Mortensen P, Mann M (November 2006). "Global, in vivo, and site-specific phosphorylation dynamics in signaling networks". Cell. 127 (3): 635–48. S2CID 7827573.
- Sugito N, Ishiguro H, Kuwabara Y, Kimura M, Mitsui A, Kurehara H, Ando T, Mori R, Takashima N, Ogawa R, Fujii Y (December 2006). "RNASEN regulates cell proliferation and affects survival in esophageal cancer patients". Clinical Cancer Research. 12 (24): 7322–8. S2CID 7569257.
- Kim YK, Kim VN (February 2007). "Processing of intronic microRNAs". The EMBO Journal. 26 (3): 775–83. PMID 17255951.
- Xing L, Kieff E (September 2007). "Epstein-Barr virus BHRF1 micro- and stable RNAs during latency III and after induction of replication". Journal of Virology. 81 (18): 9967–75. PMID 17626073.