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{{About|the protein complex|the computer processor|Microprocessor}}
{{About|the protein complex|the computer processor|Microprocessor}}
[[File:5b16 drosha dgcr8.png|thumb|right|A [[X-ray crystallography|crystal structure]] of the human [[Drosha]] protein in complex with the [[C-terminal]] [[alpha helix|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}}.]]
[[File:5b16 drosha dgcr8.png|thumb|right|A [[X-ray crystallography|crystal structure]] of the human [[Drosha]] protein in complex with the [[C-terminal]] [[alpha helix|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.<ref name=gregory /><ref name=denli /> The complex is minimally composed of the [[ribonuclease]] enzyme [[Drosha]] and the [[RNA-binding protein]] [[DGCR8]] (also known as Pasha in non-human animals), and cleaves primary miRNA [[substrate (chemistry)|substrate]]s to pre-miRNA in the [[cell nucleus]].<ref name=siomi /><ref name=wilson /><ref name=macias />
The '''microprocessor complex''' is a [[protein complex]] involved in the early stages of processing [[microRNA]] (miRNA) and [[RNA interference|RNA interference (RNAi)]] in animal cells.<ref name=gregory /><ref name=denli /> The complex is minimally composed of the [[ribonuclease]] enzyme [[Drosha]] and the dimeric [[RNA-binding protein]] [[DGCR8]] (also known as Pasha in non-human animals), and cleaves primary miRNA [[substrate (chemistry)|substrate]]s to pre-miRNA in the [[cell nucleus]].<ref name=siomi /><ref name=wilson /><ref name=macias /> Microprocessor is also the smaller of the two multi-protein complexes that compose human [[Drosha]].<ref name=":0">{{Cite journal|last=Gregory|first=Richard I.|last2=Yan|first2=Kai-ping|last3=Amuthan|first3=Govindasamy|last4=Chendrimada|first4=Thimmaiah|last5=Doratotaj|first5=Behzad|last6=Cooch|first6=Neil|last7=Shiekhattar|first7=Ramin|date=2004-11-XX|title=The Microprocessor complex mediates the genesis of microRNAs|url=http://www.nature.com/articles/nature03120|journal=Nature|language=en|volume=432|issue=7014|pages=235–240|doi=10.1038/nature03120|issn=0028-0836}}</ref>


==Composition==
==Composition==
The microprocessor complex consists minimally of two proteins: [[Drosha]], a [[ribonuclease III]] enzyme; and [[DGCR8]], a [[double-stranded RNA]] [[RNA-binding protein|binding protein]].<ref name=siomi /><ref name=wilson /><ref name=macias /> (DGCR8 is the name used in mammalian genetics, abbreviated from "[[DiGeorge syndrome]] critical region 8"; the homologous protein in [[model organism]]s such as [[Drosophila melanogaster|flies]] and [[Caenorhabditis elegans|worms]] is called ''Pasha'', for ''Pa''rtner of Dro''sha''.) The [[stoichiometry]] of the minimal complex has been experimentally difficult to determine but has been by biochemical analysis, [[single-molecule experiment]]s, and [[X-ray crystallography]]. Through these techniques the complex was concluded to be a [[protein trimer|heterotrimer]] of two DGCR8 proteins to one Drosha.<ref name=herbert /><ref name=nguyen /><ref name=kwon />
The microprocessor complex consists minimally of two proteins: [[Drosha]], a [[ribonuclease III]] enzyme; and [[DGCR8]], a [[double-stranded RNA]] [[RNA-binding protein|binding protein]].<ref name=siomi /><ref name=wilson /><ref name=macias /> (DGCR8 is the name used in mammalian genetics, abbreviated from "[[DiGeorge syndrome]] critical region 8"; the homologous protein in [[model organism]]s such as [[Drosophila melanogaster|flies]] and [[Caenorhabditis elegans|worms]] is called ''Pasha'', for ''Pa''rtner of Dro''sha''.) The [[stoichiometry]] of the minimal complex has been experimentally difficult to determine but has been by biochemical analysis, [[single-molecule experiment]]s, and [[X-ray crystallography]]. Through these techniques the complex was concluded to be a [[protein trimer|heterotrimer]] of two DGCR8 proteins to one Drosha.<ref name=herbert /><ref name=nguyen /><ref name=kwon />


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


==Function==
==Function==
[[File:3a6p xpo5 ran miRNA.png|thumb|right|The human exportin-5 protein (red) in complex with [[Ran-GTP]] (yellow) and a pre-[[microRNA]] (green), showing two-[[nucleotide]] overhang recognition element (orange). From {{PDB|3A6P}}.]]
[[File:3a6p xpo5 ran miRNA.png|thumb|right|The human exportin-5 protein (red) in complex with [[Ran-GTP]] (yellow) and a pre-[[microRNA]] (green), showing two-[[nucleotide]] overhang recognition element (orange). From {{PDB|3A6P}}.]]
Located in the [[cell nucleus]], the complex cleaves [[primary miRNA]] (pri-miRNA), typically at least 1000 [[nucleotide]]s long, into precursor miRNA (pre-miRNA).<ref>{{Cite journal|last=Michlewski|first=Gracjan|last2=Cáceres|first2=Javier F.|date=25 January 2019|title=Post-transcriptional control of miRNA biogenesis|url=http://rnajournal.cshlp.org/lookup/doi/10.1261/rna.068692.118|journal=RNA|language=en|volume=25|issue=1|pages=1–16|doi=10.1261/rna.068692.118|issn=1355-8382|pmc=6298569|pmid=30333195}}</ref> These molecules of around 70 nucleotides contain a [[stem-loop]] or hairpin structure. Pri-miRNA [[Substrate (chemistry)|substrates]] can be derived either from [[non-coding RNA]] genes or from [[intron]]s. In the latter case, there is evidence that the microprocessor complex interacts with the [[spliceosome]] and that the pri-miRNA processing occurs prior to [[RNA splicing|splicing]].<ref name=wilson /><ref name=kataoka />
Located in the [[cell nucleus]], the microprocessor complex cleaves [[primary miRNA]] (pri-miRNA), typically at least 1000 [[nucleotide]]s long, into [[Precursor mRNA|precursor miRNA]] (pre-miRNA).<ref>{{Cite journal|last=Michlewski|first=Gracjan|last2=Cáceres|first2=Javier F.|date=25 January 2019|title=Post-transcriptional control of miRNA biogenesis|url=http://rnajournal.cshlp.org/lookup/doi/10.1261/rna.068692.118|journal=RNA|language=en|volume=25|issue=1|pages=1–16|doi=10.1261/rna.068692.118|issn=1355-8382|pmc=6298569|pmid=30333195}}</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]] or hairpin structure. Pri-miRNA [[Substrate (chemistry)|substrates]] can be derived either from [[non-coding RNA]] genes or from [[intron]]s. In the latter case, there is evidence that the microprocessor complex interacts with the [[spliceosome]] and that the pri-miRNA processing occurs prior to [[RNA splicing|splicing]].<ref name=wilson /><ref name=kataoka />


[[Microprocessor complex subunit DGCR8|DGCR8]] recognizes the junctions between hairpin structures and [[single-stranded]] RNA and serves to orient [[Drosha]] to cleave around 11 nucleotides away from the junctions.<ref>{{Cite journal|last=Bellemer|first=C.|last2=Bortolin-Cavaille|first2=M.-L.|last3=Schmidt|first3=U.|last4=Jensen|first4=S. M. R.|last5=Kjems|first5=J.|last6=Bertrand|first6=E.|last7=Cavaille|first7=J.|date=2012-06-01|title=Microprocessor dynamics and interactions at endogenous imprinted C19MC microRNA genes|url=http://jcs.biologists.org/cgi/doi/10.1242/jcs.100354|journal=Journal of Cell Science|language=en|volume=125|issue=11|pages=2709–2720|doi=10.1242/jcs.100354|issn=0021-9533|doi-access=free}}</ref> Microprocessor cleavage of pri-miRNAs typically occurs co-[[transcription (biology)|transcriptionally]] 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]].<ref name=morlando /> 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]].<ref name=siomi /><ref name=wilson /><ref name=macias />
Microprocessor cleavage of pri-miRNAs typically occurs co-[[transcription (biology)|transcriptionally]] 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]].<ref name=morlando /> 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]].<ref name=siomi /><ref name=wilson /><ref name=macias />


[[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|last=Partin|first=Alexander C.|last2=Ngo|first2=Tri D.|last3=Herrell|first3=Emily|last4=Jeong|first4=Byung-Cheon|last5=Hon|first5=Gary|last6=Nam|first6=Yunsun|date=2017-11-23|title=Heme enables proper positioning of Drosha and DGCR8 on primary microRNAs|url=https://www.nature.com/articles/s41467-017-01713-y|journal=Nature Communications|language=en|volume=8|issue=1|pages=1737|doi=10.1038/s41467-017-01713-y|issn=2041-1723|pmc=PMC5700927|pmid=29170488}}</ref> [[Microprocessor complex subunit DGCR8|DGCR8]] recognizes the junctions between hairpin structures and [[single-stranded]] RNA and serves to orient [[Drosha]] to cleave around 11 [[Nucleotide|nucleotides]] away from the junctions, and is the only component to interact with the pri-miRNAs.<ref>{{Cite journal|last=Bellemer|first=C.|last2=Bortolin-Cavaille|first2=M.-L.|last3=Schmidt|first3=U.|last4=Jensen|first4=S. M. R.|last5=Kjems|first5=J.|last6=Bertrand|first6=E.|last7=Cavaille|first7=J.|date=2012-06-01|title=Microprocessor dynamics and interactions at endogenous imprinted C19MC microRNA genes|url=http://jcs.biologists.org/cgi/doi/10.1242/jcs.100354|journal=Journal of Cell Science|language=en|volume=125|issue=11|pages=2709–2720|doi=10.1242/jcs.100354|issn=0021-9533}}</ref><ref>{{Cite journal|last=Bellemer|first=C.|last2=Bortolin-Cavaille|first2=M.-L.|last3=Schmidt|first3=U.|last4=Jensen|first4=S. M. R.|last5=Kjems|first5=J.|last6=Bertrand|first6=E.|last7=Cavaille|first7=J.|date=2012-06-01|title=Microprocessor dynamics and interactions at endogenous imprinted C19MC microRNA genes|url=http://jcs.biologists.org/cgi/doi/10.1242/jcs.100354|journal=Journal of Cell Science|language=en|volume=125|issue=11|pages=2709–2720|doi=10.1242/jcs.100354|issn=0021-9533|doi-access=free}}</ref>
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.<ref name=winter /> 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]].<ref name=wilson /><ref name=winter />

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.<ref name="winter" /> 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|RNAi]].<ref name="wilson" /><ref name="winter" /> Microprocessor is also found to be involved in [[Ribosome biogenesis|ribosomal biogenesis]] specifically in the removal of [[R-loop|R-loops]] and activating transcription of ribosomal protein encoding genes.<ref>{{Cite journal|last=Jiang|first=Xuan|last2=Prabhakar|first2=Amit|last3=Van der Voorn|first3=Stephanie M.|last4=Ghatpande|first4=Prajakta|last5=Celona|first5=Barbara|last6=Venkataramanan|first6=Srivats|last7=Calviello|first7=Lorenzo|last8=Lin|first8=Chuwen|last9=Wang|first9=Wanpeng|last10=Black|first10=Brian L.|last11=Floor|first11=Stephen N.|date=2021-02-23|title=Control of ribosomal protein synthesis by the Microprocessor complex|url=https://stke.sciencemag.org/lookup/doi/10.1126/scisignal.abd2639|journal=Science Signaling|language=en|volume=14|issue=671|pages=eabd2639|doi=10.1126/scisignal.abd2639|issn=1945-0877|pmc=PMC8012103|pmid=33622983}}</ref>


==Regulation==
==Regulation==
[[Gene regulation]] by miRNA is widespread across many [[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]] and [[Microprocessor complex subunit DGCR8|DGCR8]] are subject to regulation by [[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 />
[[Gene regulation]] by miRNA is widespread across many [[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]] and [[Microprocessor complex subunit DGCR8|DGCR8]] are subject to regulation by [[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]] through association with a pri-miRNA-like hairpin structure found in the [[Microprocessor complex subunit DGCR8|DGCR8]] mRNA, which when cleaved reduces [[Microprocessor complex subunit DGCR8|DGCR8]] expression. The structure in this case is located in an [[exon]] and is unlikely to itself function as miRNA in its own right.<ref name=ha />
Microprocessor itself is auto-regulated by [[negative feedback]] through association with a pri-miRNA-like hairpin structure found in the [[Microprocessor complex subunit DGCR8|DGCR8]] mRNA, which when cleaved reduces [[Microprocessor complex subunit DGCR8|DGCR8]] expression. The structure in this case is located in an [[exon]] and is unlikely to itself function as miRNA in its own right.<ref name=ha />


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

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


== Clinical Significance ==
⚫
It has been suggested based on [[phylogenetic]] analysis that the key components of [[RNA interference]] based on exogenous substrates were present in the ancestral eukaryote, likely as an [[immune]] mechanism against [[virus]]es and [[transposable element]]s. Elaboration of this pathway for miRNA-mediated gene regulation is thought to have evolved later.<ref name=cerutti />
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|last=Beezhold|first=Kevin J|last2=Castranova|first2=Vince|last3=Chen|first3=Fei|date=2010|title=Microprocessor of microRNAs: regulation and potential for therapeutic intervention|url=http://molecular-cancer.biomedcentral.com/articles/10.1186/1476-4598-9-134|journal=Molecular Cancer|language=en|volume=9|issue=1|pages=134|doi=10.1186/1476-4598-9-134|issn=1476-4598|pmc=PMC2887798|pmid=20515486}}</ref> Microprocessor complex component, DGCR8, is affected through the [[Microdeletion|micro-deletion]] of [[22q11.2]], a small portion of [[chromosome 22]]. This deletion causes irregular processing of miRNAs which leads to [[DiGeorge syndrome|DiGeorge Syndrome]]'''.'''<ref>{{Cite journal|last=Fenelon|first=K.|last2=Mukai|first2=J.|last3=Xu|first3=B.|last4=Hsu|first4=P.-K.|last5=Drew|first5=L. J.|last6=Karayiorgou|first6=M.|last7=Fischbach|first7=G. D.|last8=MacDermott|first8=A. B.|last9=Gogos|first9=J. A.|date=2011-03-15|title=Deficiency of Dgcr8, a gene disrupted by the 22q11.2 microdeletion, results in altered short-term plasticity in the prefrontal cortex|url=http://www.pnas.org/cgi/doi/10.1073/pnas.1101219108|journal=Proceedings of the National Academy of Sciences|language=en|volume=108|issue=11|pages=4447–4452|doi=10.1073/pnas.1101219108|issn=0027-8424|pmc=PMC3060227|pmid=21368174}}</ref>


==References==
==References==

Revision as of 20:14, 18 April 2021

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) and RNA interference (RNAi) in animal cells.[1][2] The complex is minimally composed of the ribonuclease enzyme Drosha and the dimeric RNA-binding protein DGCR8 (also known as Pasha in non-human animals), and cleaves primary miRNA substrates to pre-miRNA in the cell nucleus.[3][4][5] Microprocessor is also the smaller of the two multi-protein complexes that compose human Drosha.[6]

Composition

The microprocessor complex consists minimally of two proteins: Drosha, a ribonuclease III enzyme; and DGCR8, a double-stranded RNA binding protein.[3][4][5] (DGCR8 is the name used in mammalian genetics, abbreviated from "DiGeorge syndrome critical region 8"; the homologous protein in model organisms such as flies and worms is called Pasha, for Partner of Drosha.) The stoichiometry of the minimal complex has been experimentally difficult to determine but has been by biochemical analysis, single-molecule experiments, and X-ray crystallography. Through these techniques the complex was concluded to be a heterotrimer of two DGCR8 proteins to one Drosha.[7][8][9]

In addition to the minimal catalytically active microprocessor components, other 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.[10]

Function

The human exportin-5 protein (red) in complex with Ran-GTP (yellow) and a pre-microRNA (green), showing two-nucleotide overhang recognition element (orange). From PDB: 3A6P​.

Located in the cell nucleus, the microprocessor complex cleaves primary miRNA (pri-miRNA), typically at least 1000 nucleotides long, into precursor miRNA (pre-miRNA).[11] Its two subunits have been determined as necessary and sufficient for the mediation of the development of miRNAs from the pri-miRNAs.[6] These molecules of around 70 nucleotides contain 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.[4][12]

Microprocessor cleavage of pri-miRNAs typically occurs co-transcriptionally 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.[13] 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]

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.[14] DGCR8 recognizes the junctions between hairpin structures and single-stranded RNA and serves to orient Drosha to cleave around 11 nucleotides away from the junctions, and is the only component to interact with the pri-miRNAs.[15][16]

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.[17] 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 RNAi.[4][17] Microprocessor is also found to be involved in ribosomal biogenesis specifically in the removal of R-loops and activating transcription of ribosomal protein encoding genes.[18]

Regulation

Gene regulation by miRNA is widespread across many genomes – by some estimates more than 60% of human protein-coding genes are likely to be regulated by miRNA,[19] though the quality of experimental evidence for miRNA-target interactions is often weak.[20] Because processing by microprocessor is a major determinant of miRNA abundance, microprocessor itself is then an important target of regulation.

Both Drosha and DGCR8 are subject to regulation by post-translational modifications 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.[10]

Microprocessor itself is auto-regulated by negative feedback through association with a pri-miRNA-like hairpin structure found in the DGCR8 mRNA, which when cleaved reduces DGCR8 expression. The structure in this case is located in an exon and is unlikely to itself function as miRNA in its own right.[10]

Evolution

Drosha shares striking structural similarity with the downstream ribonuclease Dicer, suggesting an evolutionary relationship, though Drosha and related enzymes are found only in animals while Dicer relatives are widely distributed, including among protozoans.[9] Both components of the microprocessor complex are conserved among the vast majority of metazoans with known genomes. Mnemiopsis leidyi, a ctenophore, lacks both Drosha and DGCR8 homologs, as well as recognizable miRNAs, and is the only known metazoan with no detectable genomic evidence of Drosha.[21] In plants, the miRNA biogenesis pathway is somewhat different; neither Drosha nor DGCR8 has a homolog in plant cells, where the first step in miRNA processing is usually executed by a different nuclear ribonuclease, DCL1, a homolog of Dicer.[10][22]

It has been suggested based on phylogenetic analysis that the key components of RNA interference based on exogenous substrates were present in the ancestral eukaryote, likely as an immune mechanism against viruses and transposable elements. Elaboration of this pathway for miRNA-mediated gene regulation is thought to have evolved later.[23]

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.[24] Microprocessor complex component, DGCR8, is affected through the micro-deletion of 22q11.2, a small portion of chromosome 22. This deletion causes irregular processing of miRNAs which leads to DiGeorge Syndrome.[25]

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. doi:10.1038/nature03120. PMID 15531877. S2CID 4389261.
  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. doi:10.1038/nature03049. PMID 15531879. S2CID 4425505.
  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. doi:10.1016/j.molcel.2010.03.013. 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. doi:10.1146/annurev-biophys-083012-130404. PMC 5895182. 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. doi:10.1042/BST20130011. hdl:1842/25877. PMID 23863141.
  6. ^ a b Gregory, Richard I.; Yan, Kai-ping; Amuthan, Govindasamy; Chendrimada, Thimmaiah; Doratotaj, Behzad; Cooch, Neil; Shiekhattar, Ramin (2004-11-XX). "The Microprocessor complex mediates the genesis of microRNAs". Nature. 432 (7014): 235–240. doi:10.1038/nature03120. ISSN 0028-0836. {{cite journal}}: Check date values in: |date= (help)
  7. ^ 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. 22 (2): 175–83. doi:10.1261/rna.054684.115. PMC 4712668. PMID 26683315.
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