The microprocessor complex is a

protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein c ...

involved in the early stages of processing

microRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miRN ...

(miRNA) and

RNA interference RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...

(RNAi) in animal cells. The complex is minimally composed of the

ribonuclease Ribonuclease (commonly abbreviated RNase) is a type of nuclease that catalyzes the degradation of RNA into smaller components. Ribonucleases can be divided into endoribonucleases and exoribonucleases, and comprise several sub-classes within ...

enzyme

Drosha Drosha is a Class 2 ribonuclease III enzyme that in humans is encoded by the ''DROSHA'' (formerly ''RNASEN'') gene. It is the primary nuclease that executes the initiation step of miRNA processing in the nucleus. It works closely with DGCR8 and ...

and the dimeric

RNA-binding protein RNA-binding proteins (often abbreviated as RBPs) are proteins that bind to the double or single stranded RNA in cells and participate in forming ribonucleoprotein complexes. RBPs contain various structural motifs, such as RNA recognition motif ( ...

DGCR8 The microprocessor complex subunit DGCR8 ''(DiGeorge syndrome critical region 8)'' is a protein that in humans is encoded by the gene. In other animals, particularly the common model organisms '' Drosophila melanogaster'' and '' Caenorhabditis ...

(also known as Pasha in non-human animals), and cleaves primary miRNA substrates to pre-miRNA in the

cell nucleus The cell nucleus (pl. nuclei; from Latin or , meaning ''kernel'' or ''seed'') is a membrane-bound organelle found in eukaryotic cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, h ...

. Microprocessor is also the smaller of the two multi-protein complexes that contain human

Composition

The microprocessor complex consists minimally of two proteins:

, a

ribonuclease III Ribonuclease III (RNase III or RNase C)(BREND3.1.26.3 is a type of ribonuclease that recognizes dsRNA and cleaves it at specific targeted locations to transform them into mature RNAs. These enzymes are a group of endoribonucleases that are char ...

enzyme; and

, a

double-stranded RNA Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydr ...

binding protein A binding protein is any protein that acts as an agent to bind two or more molecules together. Examples include: * DNA-binding protein ** Single-strand binding protein ** Telomere-binding protein *RNA-binding protein ** Poly(A)-binding protein ** ...

. (DGCR8 is the name used in mammalian genetics, abbreviated from "

DiGeorge syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent in ...

critical region 8"; the homologous protein in

model organism A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the workin ...

s such as

flies Flies are insects of the order Diptera, the name being derived from the Greek δι- ''di-'' "two", and πτερόν ''pteron'' "wing". Insects of this order use only a single pair of wings to fly, the hindwings having evolved into advanced ...

and

worms Worms may refer to: *Worm, an invertebrate animal with a tube-like body and no limbs Places *Worms, Germany Worms () is a city in Rhineland-Palatinate, Germany, situated on the Upper Rhine about south-southwest of Frankfurt am Main. It had ...

is called ''Pasha'', for ''Pa''rtner of Dro''sha''.) The

stoichiometry Stoichiometry refers to the relationship between the quantities of reactants and products before, during, and following chemical reactions. Stoichiometry is founded on the law of conservation of mass where the total mass of the reactants equal ...

of the minimal complex was at one point experimentally difficult to determine, but it has been demonstrated to be a

heterotrimer In biochemistry, a protein trimer is a macromolecular complex formed by three, usually non-covalently bound, macromolecules like proteins or nucleic acids. A homotrimer would be formed by three identical molecules. A heterotrimer would be formed ...

of two DGCR8 proteins and one Drosha. In addition to the minimal catalytically active microprocessor components, other cofactors such as DEAD box RNA helicases and

heterogeneous nuclear ribonucleoprotein Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRNA). The presence of the ...

s may be present in the complex to mediate the activity of

. Some miRNAs are processed by microprocessor only in the presence of specific cofactors.

Function

Located in the

, the microprocessor complex cleaves

primary miRNA MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transcriptional regulation of gene expression. miR ...

(pri-miRNA) into precursor miRNA (pre-miRNA). Its two subunits have been determined as necessary and sufficient for the mediation of the development of miRNAs from the pri-miRNAs. These molecules of around 70 nucleotides contain a

stem-loop Stem-loop intramolecular base pairing is a pattern that can occur in single-stranded RNA. The structure is also known as a hairpin or hairpin loop. It occurs when two regions of the same strand, usually complementary in nucleotide sequence when ...

or hairpin structure. Pri-miRNA substrates can be derived either from

non-coding RNA A non-coding RNA (ncRNA) is a functional RNA molecule that is not Translation (genetics), translated into a protein. The DNA sequence from which a functional non-coding RNA is transcribed is often called an RNA gene. Abundant and functionally im ...

genes or from

intron An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...

s. In the latter case, there is evidence that the microprocessor complex interacts with the

spliceosome A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs ( snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specif ...

and that the pri-miRNA processing occurs prior to splicing. Microprocessor cleavage of pri-miRNAs typically occurs co- transcriptionally and leaves a characteristic RNase III

single-stranded When referring to DNA transcription, the coding strand (or informational strand) is the DNA strand whose base sequence is identical to the base sequence of the RNA transcript produced (although with thymine replaced by uracil). It is this stra ...

overhang of 2-3 nucleotides, which serves as a recognition element for the transport protein

exportin-5 gene ID :57510 Exportin-5 (XPO5) is a protein that, in humans, is encoded by the ''XPO5'' gene. In eukaryotic cells, the primary purpose of XPO5 is to export pre-microRNA (also known as pre-miRNA) out of the nucleus and into the cytoplasm, for fur ...

. Pre-miRNAs are exported from the nucleus to the

cytoplasm In cell biology, the cytoplasm is all of the material within a eukaryotic cell, enclosed by the cell membrane, except for the cell nucleus. The material inside the nucleus and contained within the nuclear membrane is termed the nucleoplasm. The ...

in a

RanGTP Ran (RAs-related Nuclear protein) also known as GTP-binding nuclear protein Ran is a protein that in humans is encoded by the RAN gene. Ran is a small 25 kDa protein that is involved in transport into and out of the cell nucleus during interphase ...

-dependent manner and are further processed, typically by the

endoribonuclease An endoribonuclease is a ribonuclease endonuclease. It cleaves either single-stranded or double-stranded RNA, depending on the enzyme. Example includes both single proteins such as RNase III, RNase A, RNase T1, RNase T2 and RNase H and also com ...

enzyme

Dicer Dicer, also known as endoribonuclease Dicer or helicase with RNase motif, is an enzyme that in humans is encoded by the gene. Being part of the RNase III family, Dicer cleaves double-stranded RNA (dsRNA) and pre-microRNA (pre-miRNA) into short d ...

Hemin Hemin (haemin; ferric chloride heme) is an iron-containing porphyrin with chlorine that can be formed from a heme group, such as heme B found in the hemoglobin of human blood. Chemistry Hemin is protoporphyrin IX containing a ferric iron (Fe3 ...

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.

recognizes the junctions between hairpin structures and

RNA and serves to orient

to cleave around 11

nucleotides Nucleotides are organic molecules consisting of a nucleoside and a phosphate. They serve as monomeric units of the nucleic acid polymers – deoxyribonucleic acid (DNA) and ribonucleic acid (RNA), both of which are essential biomolecules w ...

away from the junctions, and remains in contact with the pri-miRNAs following cleavage and dissociation of Drosha. Although the large majority of miRNAs undergo processing by microprocessor, a small number of exceptions called

mirtrons Mirtrons are a type of microRNAs that are located in the introns of the mRNA encoding host genes. These short hairpin introns formed via atypical miRNA biogenesis pathways. Mirtrons arise from the spliced-out introns and are known to function in g ...

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. The processing pathways for microRNA and for exogenously derived

small interfering RNA Small interfering RNA (siRNA), sometimes known as short interfering RNA or silencing RNA, is a class of double-stranded RNA at first non-coding RNA molecules, typically 20-24 (normally 21) base pairs in length, similar to miRNA, and operating wi ...

converge at the point of

processing and are largely identical downstream. Broadly defined, both pathways constitute

RNAi RNA interference (RNAi) is a biological process in which RNA molecules are involved in sequence-specific suppression of gene expression by double-stranded RNA, through translational or transcriptional repression. Historically, RNAi was known by o ...

. 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.

Regulation

Gene regulation Regulation of gene expression, or gene regulation, includes a wide range of mechanisms that are used by cells to increase or decrease the production of specific gene products (protein or RNA). Sophisticated programs of gene expression are wi ...

by miRNA is widespread across many

genome In the fields of molecular biology and genetics, a genome is all the genetic information of an organism. It consists of nucleotide sequences of DNA (or RNA in RNA viruses). The nuclear genome includes protein-coding genes and non-coding ge ...

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

and

are subject to regulation by

post-translational modification Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosome ...

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. Microprocessor itself is auto-regulated by

negative feedback Negative feedback (or balancing feedback) occurs when some function (Mathematics), function of the output of a system, process, or mechanism is feedback, fed back in a manner that tends to reduce the fluctuations in the output, whether caused by ...

through association with a pri-miRNA-like hairpin structure found in the

mRNA, which when cleaved reduces

expression. The structure in this case is located in an

exon An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...

and is unlikely to itself function as miRNA in its own right.

Evolution

shares striking structural similarity with the downstream ribonuclease

, suggesting an evolutionary relationship, though

and related enzymes are found only in animals while Dicer relatives are widely distributed, including among

protozoan Protozoa (singular: protozoan or protozoon; alternative plural: protozoans) are a group of single-celled eukaryotes, either free-living or parasitic, that feed on organic matter such as other microorganisms or organic tissues and debris. Histo ...

s. Both components of the microprocessor complex are conserved among the vast majority of

metazoan Animals are multicellular, eukaryotic organisms in the biological kingdom Animalia. With few exceptions, animals consume organic material, breathe oxygen, are able to move, can reproduce sexually, and go through an ontogenetic stage in ...

s with known genomes. ''

Mnemiopsis leidyi ''Mnemiopsis leidyi'', the warty comb jelly or sea walnut, is a species of tentaculate ctenophore (comb jelly). It is native to western Atlantic coastal waters, but has become established as an invasive species in European and western Asian re ...

'', a ctenophore, lacks both

and

homologs, as well as recognizable miRNAs, and is the only known

with no detectable genomic evidence of

. In plants, the miRNA biogenesis pathway is somewhat different; neither Drosha nor DGCR8 has a

homolog In biology, homology is similarity due to shared ancestry between a pair of structures or genes in different taxa. A common example of homologous structures is the forelimbs of vertebrates, where the wings of bats and birds, the arms of prima ...

in plant cells, where the first step in miRNA processing is usually executed by a different

nuclear Nuclear may refer to: Physics Relating to the nucleus of the atom: * Nuclear engineering *Nuclear physics *Nuclear power *Nuclear reactor *Nuclear weapon *Nuclear medicine *Radiation therapy *Nuclear warfare Mathematics *Nuclear space *Nuclear ...

DCL1 DCL1 (an abbreviation of Dicer-like 1) is a gene in plants that codes for the DCL1 protein, a ribonuclease III enzyme involved in processing double-stranded RNA (dsRNA) and microRNA (miRNA). Although DCL1, also called Endoribonuclease Dicer homolog ...

, a homolog of

. It has been suggested based on

phylogenetic In biology, phylogenetics (; from Greek φυλή/ φῦλον [] "tribe, clan, race", and wikt:γενετικός, γενετικός [] "origin, source, birth") is the study of the evolutionary history and relationships among or within groups o ...

analysis that the key components of

based on exogenous substrates were present in the ancestral

eukaryote Eukaryotes () are organisms whose cells have a nucleus. All animals, plants, fungi, and many unicellular organisms, are Eukaryotes. They belong to the group of organisms Eukaryota or Eukarya, which is one of the three domains of life. Bacte ...

, likely as an

immune In biology, immunity is the capability of multicellular organisms to resist harmful microorganisms. Immunity involves both specific and nonspecific components. The nonspecific components act as barriers or eliminators of a wide range of pathogens ...

mechanism against

virus A virus is a submicroscopic infectious agent that replicates only inside the living cells of an organism. Viruses infect all life forms, from animals and plants to microorganisms, including bacteria and archaea. Since Dmitri Ivanovsky's 1 ...

es and

transposable element A transposable element (TE, transposon, or jumping gene) is a nucleic acid sequence in DNA that can change its position within a genome, sometimes creating or reversing mutations and altering the cell's genetic identity and genome size. Transp ...

s. Elaboration of this pathway for miRNA-mediated gene regulation is thought to have evolved later.

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. Microprocessor complex component, DGCR8, is affected through the micro-deletion of

22q11.2 DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent i ...

, a small portion of

chromosome 22 Chromosome 22 is one of the 23 pairs of chromosomes in human cell (biology), cells. Humans normally have two copies of chromosome 22 in each cell. Chromosome 22 is the second smallest human chromosome, spanning about 49 million DNA base pairs and ...

. This deletion causes irregular processing of miRNAs which leads to

DiGeorge Syndrome DiGeorge syndrome, also known as 22q11.2 deletion syndrome, is a syndrome caused by a microdeletion on the long arm of chromosome 22. While the symptoms can vary, they often include congenital heart problems, specific facial features, frequent in ...

References

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