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Microprocessor complex

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This article is about the protein complex. For the computer processor, see Microprocessor.
A crystal structure of the human Drosha protein in complex with the C-terminal helices of two DGCR8 molecules (green). Drosha consists of two ribonuclease III domains (blue and orange); a double-stranded RNA binding domain (yellow); and a connector/platform domain (gray) containing two bound zinc ion (spheres). From PDB: 5B16​.

The Microprocessor complex is a protein complex involved in the early stages of processing microRNA (miRNA) in animal cells.[1][2] The complex is minimally composed of the ribonuclease enzyme Drosha and the RNA-binding protein DGCR8 (also known as Pasha) and cleaves primary miRNA substrates to pre-miRNA in the cell nucleus.[3][4][5] Neither protein has a homolog in plant cells, where the first step in miRNA processing is usually executed by a different nuclear ribonuclease, DCL1.[6][7]

Composition

The Microprocessor complex consists minimally of two proteins: Drosha, a ribonuclease III enzyme; and DGCR8 (also known as Pasha), a double-stranded RNA binding protein.[3][4][5] The stoichiometry of the minimal complex has been experimentally difficult to determine, but has been determined by biochemical analysis, single-molecule experiments, and X-ray crystallography to be a heterotrimer of two DCGR8 proteins to one Drosha.[8][9][10]

In addition to the minimal catalytically active Microprocessor components, additional cofactors such as DEAD box RNA helicases and heterogeneous nuclear ribonucleoproteins may be present in the complex to mediate the activity of Drosha.[3] Some miRNAs are processed by Microprocessor only in the presence of specific cofactors.[6]

Function

Located in the cell nucleus, the complex cleaves primary miRNA (pri-miRNA), typically at least 1000 nucleotides long, into precursor miRNA (pre-miRNA) molecules of around 70 nucleotides containing a stem-loop or hairpin structure. Pri-miRNA substrates can be derived either from non-coding RNA genes or from introns. In the latter case, there is evidence that the Microprocessor complex interacts with the spliceosome and that the pri-miRNA processing occurs prior to splicing.[11][4]

DCGR8 recognizes the junctions between hairpin structures and single-stranded RNA and serves to orient Drosha to cleave around 11 nucleotides away from the junctions. Microprocessor cleavage of pri-miRNAs typically occurs co-transcriptionally[12] and leaves a characteristic RNase III single-stranded overhang of 2-3 nucleotides, which serves as a recognition element for the transport protein exportin-5. Pre-miRNAs are exported from the nucleus to the cytoplasm in a RanGTP-dependent manner and are further processed, typically by the endoribonuclease enzyme Dicer.[3][4][5]

Although the large majority of miRNAs undergo processing by Microprocessor, a small number of exceptions called mirtrons have been described; these are very small introns which, after splicing, have the appropriate size and stem-loop structure to serve as a pre-miRNA.[13] The processing pathways for microRNA and for exogenously derived small interfering RNA converge at the point of Dicer processing and are largely identical downstream. Broadly defined, both pathways constitute RNA interference.[4][13]

References

  1. ^ Gregory, RI; Yan, KP; Amuthan, G; Chendrimada, T; Doratotaj, B; Cooch, N; Shiekhattar, R (11 November 2004). "The Microprocessor complex mediates the genesis of microRNAs". Nature. 432 (7014): 235–40. PMID 15531877.
  2. ^ Denli, AM; Tops, BB; Plasterk, RH; Ketting, RF; Hannon, GJ (11 November 2004). "Processing of primary microRNAs by the Microprocessor complex". Nature. 432 (7014): 231–5. PMID 15531879.
  3. ^ a b c d Siomi, H; Siomi, MC (14 May 2010). "Posttranscriptional regulation of microRNA biogenesis in animals". Molecular cell. 38 (3): 323–32. PMID 20471939.
  4. ^ a b c d e Wilson, RC; Doudna, JA (2013). "Molecular mechanisms of RNA interference". Annual review of biophysics. 42: 217–39. PMID 23654304.
  5. ^ a b c Macias, S; Cordiner, RA; Cáceres, JF (August 2013). "Cellular functions of the microprocessor". Biochemical Society transactions. 41 (4): 838–43. PMID 23863141.
  6. ^ a b Ha, M; Kim, VN (August 2014). "Regulation of microRNA biogenesis". Nature reviews. Molecular cell biology. 15 (8): 509–24. PMID 25027649.
  7. ^ Axtell, MJ; Westholm, JO; Lai, EC (2011). "Vive la différence: biogenesis and evolution of microRNAs in plants and animals". Genome biology. 12 (4): 221. PMID 21554756.
  8. ^ Herbert, KM; Sarkar, SK; Mills, M; Delgado De la Herran, HC; Neuman, KC; Steitz, JA (February 2016). "A heterotrimer model of the complete Microprocessor complex revealed by single-molecule subunit counting". RNA (New York, N.Y.). 22 (2): 175–83. PMID 26683315.
  9. ^ Nguyen, TA; Jo, MH; Choi, YG; Park, J; Kwon, SC; Hohng, S; Kim, VN; Woo, JS (4 June 2015). "Functional Anatomy of the Human Microprocessor". Cell. 161 (6): 1374–87. PMID 26027739.
  10. ^ Kwon, SC; Nguyen, TA; Choi, YG; Jo, MH; Hohng, S; Kim, VN; Woo, JS (14 January 2016). "Structure of Human DROSHA". Cell. 164 (1–2): 81–90. PMID 26748718.
  11. ^ Kataoka, N; Fujita, M; Ohno, M (June 2009). "Functional association of the Microprocessor complex with the spliceosome". Molecular and cellular biology. 29 (12): 3243–54. PMID 19349299.
  12. ^ Morlando, M; Ballarino, M; Gromak, N; Pagano, F; Bozzoni, I; Proudfoot, NJ (September 2008). "Primary microRNA transcripts are processed co-transcriptionally". Nature structural & molecular biology. 15 (9): 902–9. PMID 19172742.
  13. ^ a b Winter, J; Jung, S; Keller, S; Gregory, RI; Diederichs, S (March 2009). "Many roads to maturity: microRNA biogenesis pathways and their regulation". Nature cell biology. 11 (3): 228–34. PMID 19255566.
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