# Microprocessor complex

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{{Short description|Protein involved in processing RNA in animal cells}}
{{About|the protein complex|the computer processor|Microprocessor}}
[[File:6v5b.png|thumb|right|A [cryo-electron microscopy](/source/cryo-electron_microscopy) structure of the microprocessor complex, showing human [Drosha](/source/Drosha) protein ([ribonuclease III](/source/ribonuclease_III), green) and two subunits of [DGCR8](/source/DGCR8) (dark and light blue) interacting with and ready to cleave a primary [microRNA](/source/microRNA). From {{PDB|6V5B}}.<ref name="partin_2020">{{cite journal |last1=Partin |first1=Alexander C. |last2=Zhang |first2=Kaiming |last3=Jeong |first3=Byung-Cheon |last4=Herrell |first4=Emily |last5=Li |first5=Shanshan |last6=Chiu |first6=Wah |last7=Nam |first7=Yunsun |title=Cryo-EM Structures of Human Drosha and DGCR8 in Complex with Primary MicroRNA |journal=Molecular Cell |date=May 2020 |volume=78 |issue=3 |pages=411–422.e4 |doi=10.1016/j.molcel.2020.02.016|pmid=32220646 |pmc=7214211 }}</ref>]]

The '''microprocessor complex''' is a [protein complex](/source/protein_complex) involved in the early stages of processing [microRNA](/source/microRNA) (miRNA) and [RNA interference](/source/RNA_interference) (RNAi) in animal cells.<ref name=gregory /><ref name=denli /> The complex is minimally composed of the [ribonuclease](/source/ribonuclease) enzyme [Drosha](/source/Drosha) and the dimeric  [RNA-binding protein](/source/RNA-binding_protein) [DGCR8](/source/DGCR8) (also known as Pasha in non-human animals), and cleaves primary miRNA [substrate](/source/substrate_(chemistry))s to pre-miRNA in the [cell nucleus](/source/cell_nucleus).<ref name=siomi /><ref name=wilson /><ref name=macias /> Microprocessor is also the smaller of the two multi-protein complexes that contain human [Drosha](/source/Drosha).<ref name=":0">{{cite journal | vauthors = Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R | title = The Microprocessor complex mediates the genesis of microRNAs | journal = Nature | volume = 432 | issue = 7014 | pages = 235–40 | date = November 2004 | pmid = 15531877 | doi = 10.1038/nature03120 | bibcode = 2004Natur.432..235G | s2cid = 4389261 }}</ref>

[[File:5b16 drosha dgcr8.png|thumb|right|A [crystal structure](/source/X-ray_crystallography) of the human [Drosha](/source/Drosha) protein in complex with the [C-terminal](/source/C-terminal) [helices](/source/alpha_helix) of two [DGCR8](/source/DGCR8) molecules (green). Drosha consists of two [ribonuclease III](/source/ribonuclease_III) domains (blue and orange); a double-stranded RNA binding domain (yellow); and a connector/platform domain (gray) containing two bound [zinc](/source/zinc) ion (spheres). From {{PDB|5B16}}.<ref name=kwon />]]

==Composition==
The microprocessor complex consists minimally of two proteins: [Drosha](/source/Drosha), a [ribonuclease III](/source/ribonuclease_III) enzyme; and [DGCR8](/source/DGCR8), a [double-stranded RNA](/source/double-stranded_RNA) [binding protein](/source/RNA-binding_protein).<ref name=siomi /><ref name=wilson /><ref name=macias /> (DGCR8 is the name used in mammalian genetics, abbreviated from "[DiGeorge syndrome](/source/DiGeorge_syndrome) critical region 8"; the homologous protein in [model organism](/source/model_organism)s such as [flies](/source/Drosophila_melanogaster) and [worms](/source/Caenorhabditis_elegans) is called ''Pasha'', for ''Pa''rtner of Dro''sha''.) The [stoichiometry](/source/stoichiometry) of the minimal complex was at one point experimentally difficult to determine, but it has been demonstrated to be a [heterotrimer](/source/protein_trimer) of two DGCR8 proteins and one Drosha.<ref name=partin_2020 /><ref name=kwon /><ref name=herbert /><ref name=nguyen />

In addition to the minimal catalytically active microprocessor components, other cofactors such as [DEAD box RNA helicases](/source/DEAD%2FDEAH_box_helicase) and [heterogeneous nuclear ribonucleoprotein](/source/heterogeneous_nuclear_ribonucleoprotein)s may be present in the complex to mediate the activity of [Drosha](/source/Drosha).<ref name=siomi /> Some miRNAs are processed by microprocessor only in the presence of specific cofactors.<ref name=ha />

== Function ==
[[File:3a6p xpo5 ran miRNA.png|thumb|right|The human exportin-5 protein (red) in complex with [Ran-GTP](/source/Ran-GTP) (yellow) and a pre-[microRNA](/source/microRNA) (green), showing two-[nucleotide](/source/nucleotide) overhang recognition element (orange). From {{PDB|3A6P}}.<ref name="okada_2009">{{cite journal |last1=Okada |first1=Chimari |last2=Yamashita |first2=Eiki |last3=Lee |first3=Soo Jae |last4=Shibata |first4=Satoshi |last5=Katahira |first5=Jun |last6=Nakagawa |first6=Atsushi |last7=Yoneda |first7=Yoshihiro |last8=Tsukihara |first8=Tomitake |title=A High-Resolution Structure of the Pre-microRNA Nuclear Export Machinery |journal=Science |date=2009-11-27 |volume=326 |issue=5957 |pages=1275–1279 |doi=10.1126/science.1178705|pmid=19965479 |bibcode=2009Sci...326.1275O |s2cid=206522317 }}</ref>]]
Located in the [cell nucleus](/source/cell_nucleus), the microprocessor complex cleaves [primary miRNA](/source/primary_miRNA) (pri-miRNA) into [precursor miRNA](/source/Precursor_mRNA) (pre-miRNA).<ref>{{cite journal | vauthors = Michlewski G, Cáceres JF | title = Post-transcriptional control of miRNA biogenesis | journal = RNA | volume = 25 | issue = 1 | pages = 1–16 | date = January 2019 | pmid = 30333195 | pmc = 6298569 | doi = 10.1261/rna.068692.118 }}</ref> Its two subunits have been determined as necessary and sufficient for the mediation of the development of miRNAs from the pri-miRNAs.<ref name=":0" /> These molecules of around 70 nucleotides contain a [stem-loop](/source/stem-loop) or hairpin structure. Pri-miRNA [substrates](/source/Substrate_(chemistry)) can be derived either from [non-coding RNA](/source/non-coding_RNA) genes or from [intron](/source/intron)s. In the latter case, there is evidence that the microprocessor complex interacts with the [spliceosome](/source/spliceosome) and that the pri-miRNA processing occurs prior to [splicing](/source/RNA_splicing).<ref name=wilson /><ref name=kataoka />

Microprocessor cleavage of pri-miRNAs typically occurs co-[transcriptionally](/source/transcription_(biology)) and leaves a characteristic RNase III [single-stranded](/source/single-stranded) overhang of 2-3 nucleotides, which serves as a recognition element for the transport protein [exportin-5](/source/exportin-5).<ref name=morlando /> Pre-miRNAs are exported from the nucleus to the [cytoplasm](/source/cytoplasm) in a [RanGTP](/source/RanGTP)-dependent manner and are further processed, typically by the [endoribonuclease](/source/endoribonuclease) enzyme [Dicer](/source/Dicer).<ref name=siomi /><ref name=wilson /><ref name=macias />

[Hemin](/source/Hemin) allows for the increased processing of pri-miRNAs through an induced conformational change of the DGCR8 subunit, and also enhances DGCR8's binding specificity for RNA.<ref>{{cite journal | vauthors = Partin AC, Ngo TD, Herrell E, Jeong BC, Hon G, Nam Y | title = Heme enables proper positioning of Drosha and DGCR8 on primary microRNAs | journal = Nature Communications | volume = 8 | issue = 1 | article-number = 1737 | date = November 2017 | pmid = 29170488 | pmc = 5700927 | doi = 10.1038/s41467-017-01713-y | bibcode = 2017NatCo...8.1737P }}</ref> [DGCR8](/source/Microprocessor_complex_subunit_DGCR8) recognizes the junctions between hairpin structures and [single-stranded](/source/single-stranded) RNA and serves to orient [Drosha](/source/Drosha) to cleave around 11 [nucleotides](/source/Nucleotide) away from the junctions, and remains in contact with the pri-miRNAs following cleavage and dissociation of Drosha.<ref name=bellemer_2012>{{cite journal | vauthors = Bellemer C, Bortolin-Cavaillé ML, Schmidt U, Jensen SM, Kjems J, Bertrand E, Cavaillé J | title = Microprocessor dynamics and interactions at endogenous imprinted C19MC microRNA genes | journal = Journal of Cell Science | volume = 125 | issue = Pt 11 | pages = 2709–20 | date = June 2012 | article-number = jcs.100354 | pmid = 22393237 | doi = 10.1242/jcs.100354 | doi-broken-date = 13 November 2025 | s2cid = 19121670 | doi-access = free }}</ref>

Although the large majority of miRNAs undergo processing by microprocessor, a small number of exceptions called [mirtrons](/source/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.<ref name="winter" /> The processing pathways for microRNA and for exogenously derived [small interfering RNA](/source/small_interfering_RNA) converge at the point of [Dicer](/source/Dicer) processing and are largely identical downstream. Broadly defined, both pathways constitute [RNAi](/source/RNA_interference).<ref name="wilson" /><ref name="winter" /> Microprocessor is also found to be involved in [ribosomal biogenesis](/source/Ribosome_biogenesis) specifically in the removal of [R-loops](/source/R-loop) and activating transcription of ribosomal protein encoding genes.<ref>{{cite journal | vauthors = Jiang X, Prabhakar A, Van der Voorn SM, Ghatpande P, Celona B, Venkataramanan S, Calviello L, Lin C, Wang W, Black BL, Floor SN, Lagna G, Hata A | display-authors = 6 | title = Control of ribosomal protein synthesis by the Microprocessor complex | journal = Science Signaling | volume = 14 | issue = 671 | article-number = eabd2639 | date = February 2021 | pmid = 33622983 | pmc = 8012103 | doi = 10.1126/scisignal.abd2639 }}</ref>

==Regulation==
[Gene regulation](/source/Gene_regulation) by miRNA is widespread across many [genome](/source/genome)s – by some estimates more than 60% of human protein-coding genes are likely to be regulated by miRNA,<ref name=friedman /> though the quality of experimental evidence for miRNA-target interactions is often weak.<ref name=lee /> Because processing by microprocessor is a major determinant of miRNA abundance, microprocessor itself is then an important target of regulation. 

Both [Drosha](/source/Drosha) and [DGCR8](/source/Microprocessor_complex_subunit_DGCR8) are subject to regulation by [post-translational modification](/source/post-translational_modification)s modulating stability, intracellular localization, and activity levels. Activity against particular substrates may be regulated by additional protein cofactors interacting with the microprocessor complex. The loop region of the pri-miRNA stem-loop is also a recognition element for regulatory proteins, which may up- or down-regulate microprocessor processing of the specific miRNAs they target.<ref name="ha" />

Microprocessor itself is auto-regulated by [negative feedback](/source/negative_feedback) through association with a pri-miRNA-like hairpin structure found in the [DGCR8](/source/Microprocessor_complex_subunit_DGCR8) mRNA, which when cleaved reduces [DGCR8](/source/Microprocessor_complex_subunit_DGCR8) expression. The structure in this case is located in an [exon](/source/exon) and is unlikely to itself function as miRNA in its own right.<ref name=ha />

==Evolution==
[Drosha](/source/Drosha) shares striking structural similarity with the downstream ribonuclease [Dicer](/source/Dicer), suggesting an evolutionary relationship, though [Drosha](/source/Drosha) and related enzymes are found only in animals while Dicer relatives are widely distributed, including among [protozoan](/source/protozoan)s.<ref name=kwon /> Both components of the microprocessor complex are [conserved](/source/sequence_conservation) among the vast majority of [metazoan](/source/metazoan)s with known genomes. ''[Mnemiopsis leidyi](/source/Mnemiopsis_leidyi)'', a [ctenophore](/source/ctenophore), lacks both [Drosha](/source/Drosha) and [DGCR8](/source/Microprocessor_complex_subunit_DGCR8) homologs, as well as recognizable miRNAs, and is the only known [metazoan](/source/metazoan) with no detectable genomic evidence of [Drosha](/source/Drosha).<ref name=maxwell /> In plants, the miRNA biogenesis pathway is somewhat different; neither Drosha nor DGCR8 has a [homolog](/source/homology_(biology)) in plant cells, where the first step in miRNA processing is usually executed by a different [nuclear](/source/Cell_nucleus) [ribonuclease](/source/ribonuclease), [DCL1](/source/DCL1), a homolog of [Dicer](/source/Dicer).<ref name=ha /><ref name=axtell />

It has been suggested based on [phylogenetic](/source/phylogenetic) analysis that the key components of [RNA interference](/source/RNA_interference) based on exogenous [substrates](/source/Substrate_(chemistry)) were present in the ancestral [eukaryote](/source/eukaryote), likely as an [immune](/source/immune) mechanism against [virus](/source/virus)es and [transposable element](/source/transposable_element)s. Elaboration of this pathway for miRNA-mediated gene regulation is thought to have evolved later.<ref name=cerutti />

== Clinical significance ==
The involvement of miRNAs in diseases has led scientists to become more interested in the role of additional protein complexes, like microprocessor, that have the ability to influence or modulate the function and expression of miRNAs.<ref>{{cite journal | vauthors = Beezhold KJ, Castranova V, Chen F | title = Microprocessor of microRNAs: regulation and potential for therapeutic intervention | journal = Molecular Cancer | volume = 9 | issue = 1 | article-number = 134 | date = June 2010 | pmid = 20515486 | pmc = 2887798 | doi = 10.1186/1476-4598-9-134 | doi-access = free }}</ref> Microprocessor complex component, DGCR8, is affected through the [micro-deletion](/source/Microdeletion) of [22q11.2](/source/22q11.2), a small portion of [chromosome 22](/source/chromosome_22). This deletion causes irregular processing of miRNAs which leads to [DiGeorge Syndrome](/source/DiGeorge_syndrome)'''.'''<ref>{{cite journal | vauthors = Fénelon K, Mukai J, Xu B, Hsu PK, Drew LJ, Karayiorgou M, Fischbach GD, Macdermott AB, Gogos JA | display-authors = 6 | title = Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 108 | issue = 11 | pages = 4447–52 | date = March 2011 | pmid = 21368174 | pmc = 3060227 | doi = 10.1073/pnas.1101219108 | bibcode = 2011PNAS..108.4447F | doi-access = free }}</ref>

== References ==
{{reflist|30em|refs=
<ref name="gregory">{{cite journal | vauthors = Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R | title = The Microprocessor complex mediates the genesis of microRNAs | journal = Nature | volume = 432 | issue = 7014 | pages = 235–40 | date = November 2004 | pmid = 15531877 | doi = 10.1038/nature03120 | bibcode = 2004Natur.432..235G | s2cid = 4389261 }}</ref>
<ref name="denli">{{cite journal | vauthors = Denli AM, Tops BB, Plasterk RH, Ketting RF, Hannon GJ | title = Processing of primary microRNAs by the Microprocessor complex | journal = Nature | volume = 432 | issue = 7014 | pages = 231–5 | date = November 2004 | pmid = 15531879 | doi = 10.1038/nature03049 | bibcode = 2004Natur.432..231D | s2cid = 4425505 }}</ref>
<ref name="herbert">{{cite journal | vauthors = Herbert KM, Sarkar SK, Mills M, Delgado De la Herran HC, Neuman KC, Steitz JA | title = A heterotrimer model of the complete Microprocessor complex revealed by single-molecule subunit counting | journal = RNA | volume = 22 | issue = 2 | pages = 175–83 | date = February 2016 | pmid = 26683315 | pmc = 4712668 | doi = 10.1261/rna.054684.115 }}</ref>
<ref name="nguyen">{{cite journal | vauthors = Nguyen TA, Jo MH, Choi YG, Park J, Kwon SC, Hohng S, Kim VN, Woo JS | display-authors = 6 | title = Functional Anatomy of the Human Microprocessor | journal = Cell | volume = 161 | issue = 6 | pages = 1374–87 | date = June 2015 | pmid = 26027739 | doi = 10.1016/j.cell.2015.05.010 | doi-access = free }}</ref>
<ref name="kwon">{{cite journal | vauthors = Kwon SC, Nguyen TA, Choi YG, Jo MH, Hohng S, Kim VN, Woo JS | title = Structure of Human DROSHA | journal = Cell | volume = 164 | issue = 1–2 | pages = 81–90 | date = January 2016 | pmid = 26748718 | doi = 10.1016/j.cell.2015.12.019 | doi-access = free }}</ref>
<ref name="kataoka">{{cite journal | vauthors = Kataoka N, Fujita M, Ohno M | title = Functional association of the Microprocessor complex with the spliceosome | journal = Molecular and Cellular Biology | volume = 29 | issue = 12 | pages = 3243–54 | date = June 2009 | pmid = 19349299 | pmc = 2698730 | doi = 10.1128/MCB.00360-09 }}</ref>
<ref name="wilson">{{cite journal | vauthors = Wilson RC, Doudna JA | title = Molecular mechanisms of RNA interference | journal = Annual Review of Biophysics | volume = 42 | pages = 217–39 | date = 2013 | pmid = 23654304 | pmc = 5895182 | doi = 10.1146/annurev-biophys-083012-130404 }}</ref>
<ref name="morlando">{{cite journal | vauthors = Morlando M, Ballarino M, Gromak N, Pagano F, Bozzoni I, Proudfoot NJ | title = Primary microRNA transcripts are processed co-transcriptionally | journal = Nature Structural & Molecular Biology | volume = 15 | issue = 9 | pages = 902–9 | date = September 2008 | pmid = 19172742 | pmc = 6952270 | doi = 10.1038/nsmb.1475 }}</ref>
<ref name="winter">{{cite journal | vauthors = Winter J, Jung S, Keller S, Gregory RI, Diederichs S | title = Many roads to maturity: microRNA biogenesis pathways and their regulation | journal = Nature Cell Biology | volume = 11 | issue = 3 | pages = 228–34 | date = March 2009 | pmid = 19255566 | doi = 10.1038/ncb0309-228 | s2cid = 205286318 }}</ref>
<ref name="siomi">{{cite journal | vauthors = Siomi H, Siomi MC | title = Posttranscriptional regulation of microRNA biogenesis in animals | journal = Molecular Cell | volume = 38 | issue = 3 | pages = 323–32 | date = May 2010 | pmid = 20471939 | doi = 10.1016/j.molcel.2010.03.013 | doi-access = free }}</ref>
<ref name="macias">{{cite journal | vauthors = Macias S, Cordiner RA, Cáceres JF | title = Cellular functions of the microprocessor | journal = Biochemical Society Transactions | volume = 41 | issue = 4 | pages = 838–43 | date = August 2013 | pmid = 23863141 | doi = 10.1042/BST20130011 | hdl-access = free | hdl = 1842/25877 }}</ref>
<ref name="ha">{{cite journal | vauthors = Ha M, Kim VN | title = Regulation of microRNA biogenesis | journal = Nature Reviews. Molecular Cell Biology | volume = 15 | issue = 8 | pages = 509–24 | date = August 2014 | pmid = 25027649 | doi = 10.1038/nrm3838 | s2cid = 205495632 }}</ref>
<ref name="axtell">{{cite journal | vauthors = Axtell MJ, Westholm JO, Lai EC | title = Vive la différence: biogenesis and evolution of microRNAs in plants and animals | journal = Genome Biology | volume = 12 | issue = 4 | page = 221 | date = 2011 | pmid = 21554756 | pmc = 3218855 | doi = 10.1186/gb-2011-12-4-221 | doi-access = free }}</ref>
<ref name="friedman">{{cite journal | vauthors = Friedman RC, Farh KK, Burge CB, Bartel DP | title = Most mammalian mRNAs are conserved targets of microRNAs | journal = Genome Research | volume = 19 | issue = 1 | pages = 92–105 | date = January 2009 | pmid = 18955434 | pmc = 2612969 | doi = 10.1101/gr.082701.108 }}</ref>
<ref name="lee">{{cite journal | vauthors = Lee YJ, Kim V, Muth DC, Witwer KW | title = Validated MicroRNA Target Databases: An Evaluation | journal = Drug Development Research | volume = 76 | issue = 7 | pages = 389–96 | date = November 2015 | pmid = 26286669 | pmc = 4777876 | doi = 10.1002/ddr.21278 }}</ref>
<ref name="maxwell">{{cite journal | vauthors = Maxwell EK, Ryan JF, Schnitzler CE, Browne WE, Baxevanis AD | title = MicroRNAs and essential components of the microRNA processing machinery are not encoded in the genome of the ctenophore Mnemiopsis leidyi | journal = BMC Genomics | volume = 13 | article-number = 714 | date = December 2012 | pmid = 23256903 | pmc = 3563456 | doi = 10.1186/1471-2164-13-714 | doi-access = free }}</ref>
<ref name="cerutti">{{cite journal | vauthors = Cerutti H, Casas-Mollano JA | title = On the origin and functions of RNA-mediated silencing: from protists to man | journal = Current Genetics | volume = 50 | issue = 2 | pages = 81–99 | date = August 2006 | pmid = 16691418 | pmc = 2583075 | doi = 10.1007/s00294-006-0078-x }}</ref>
}}

Category:MicroRNA
Category:RNA interference
Category:Gene expression
Category:Protein complexes

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Adapted from the Wikipedia article [Microprocessor complex](https://en.wikipedia.org/wiki/Microprocessor_complex) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Microprocessor_complex?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.