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Drosha is a Class 2 ribonuclease III
enzyme An enzyme () is a protein that acts as a biological catalyst by accelerating chemical reactions. The molecules upon which enzymes may act are called substrate (chemistry), substrates, and the enzyme converts the substrates into different mol ...
that in humans is encoded by the ''DROSHA'' (formerly ''RNASEN'')
gene In biology, the word gene has two meanings. The Mendelian gene is a basic unit of heredity. The molecular gene is a sequence of nucleotides in DNA that is transcribed to produce a functional RNA. There are two types of molecular genes: protei ...
. 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 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 shor ...
. It has been found significant in clinical knowledge for cancer prognosis. and HIV-1 replication.


History

Human Drosha was cloned in 2000 when it was identified as a nuclear dsRNA ribonuclease involved in the processing of
ribosomal RNA Ribosomal ribonucleic acid (rRNA) is a type of non-coding RNA which is the primary component of ribosomes, essential to all cells. rRNA is a ribozyme which carries out protein synthesis in ribosomes. Ribosomal RNA is transcribed from ribosomal ...
precursors. The other two human enzymes that participate in the processing and activity of miRNA are the
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 shor ...
and Argonaute proteins. Recently, proteins like Drosha have been found significant in cancer prognosis and HIV-1 replication.


Function

Members of the ribonuclease III superfamily of double-stranded (ds)
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
-specific
endoribonuclease In biochemistry, an endoribonuclease is a class of enzyme which is a type of ribonuclease (an RNA cleaver), itself a type of endonuclease (a nucleotide cleaver). It cleaves either single-stranded or double-stranded RNA, depending on the enzyme. Ex ...
s participate in diverse
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
maturation and decay pathways in
eukaryotic The eukaryotes ( ) constitute the Domain (biology), domain of Eukaryota or Eukarya, organisms whose Cell (biology), cells have a membrane-bound cell nucleus, nucleus. All animals, plants, Fungus, fungi, seaweeds, and many unicellular organisms ...
and
prokaryotic A prokaryote (; less commonly spelled procaryote) is a single-celled organism whose cell lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Ancient Greek (), meaning 'before', and (), meaning 'nut' ...
cells. The RNase III Drosha is the core
nuclease In biochemistry, a nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds that link nucleotides together to form nucleic acids. Nucleases variously affect single and ...
that executes the initiation step of
microRNA Micro ribonucleic acid (microRNA, miRNA, μRNA) are small, single-stranded, non-coding RNA molecules containing 21–23 nucleotides. Found in plants, animals, and even some viruses, miRNAs are involved in RNA silencing and post-transcr ...
(miRNA) processing in the nucleus. The microRNAs thus generated are short
RNA Ribonucleic acid (RNA) is a polymeric molecule that is essential for most biological functions, either by performing the function itself (non-coding RNA) or by forming a template for the production of proteins (messenger RNA). RNA and deoxyrib ...
molecules that regulate a wide variety of other genes by interacting with the
RNA-induced silencing complex The RNA-induced silencing complex, or RISC, is a multiprotein complex, specifically a ribonucleoprotein, which functions in gene silencing via a variety of pathways at the transcriptional and translational levels. Using single-stranded RNA (ssRNA) ...
(RISC) to induce cleavage of complementary
messenger RNA In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of synthesizing a protein. mRNA is created during the ...
(mRNA) as part of the
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 ...
pathway. MicroRNA molecules are synthesized as long RNA
primary transcript A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNA ...
s known as a ''pri-miRNAs'', which are cleaved by Drosha to produce a characteristic
stem-loop Stem-loops are nucleic acid Biomolecular structure, secondary structural elements which form via intramolecular base pairing in single-stranded DNA or RNA. They are also referred to as hairpins or hairpin loops. A stem-loop occurs when two regi ...
structure of about 70
base pair A base pair (bp) is a fundamental unit of double-stranded nucleic acids consisting of two nucleobases bound to each other by hydrogen bonds. They form the building blocks of the DNA double helix and contribute to the folded structure of both DNA ...
s long, known as a ''pre-miRNA.'' Pre-miRNAs, when associated with EXP5, are stabilized due to removal of the 5' cap and 3' poly(A) tail. Drosha exists as part of a
protein complex A protein complex or multiprotein complex is a group of two or more associated polypeptide chains. Protein complexes are distinct from multidomain enzymes, in which multiple active site, catalytic domains are found in a single polypeptide chain. ...
called the Microprocessor complex, which also contains the double-stranded RNA binding protein DGCR8 (called
Pasha Pasha (; ; ) was a high rank in the Ottoman Empire, Ottoman political and military system, typically granted to governors, generals, dignitary, dignitaries, and others. ''Pasha'' was also one of the highest titles in the 20th-century Kingdom of ...
in '' D. melanogaster'' and '' C. elegans''). DGCR8 is essential for Drosha activity and is capable of binding single-stranded fragments of the pri-miRNA that are required for proper processing. The Drosha complex also contains several auxiliary factors such as EWSR1, FUS, hnRNPs, p68, and p72. Both Drosha and DGCR8 are localized to the
cell nucleus The cell nucleus (; : nuclei) is a membrane-bound organelle found in eukaryote, eukaryotic cell (biology), cells. Eukaryotic cells usually have a single nucleus, but a few cell types, such as mammalian red blood cells, have #Anucleated_cells, ...
, where processing of pri-miRNA to pre-miRNA occurs. These two proteins homeostatically control miRNA biogenesis by an auto-feedback loop. A 2nt 3' overhang is generated by Drosha in the nucleus recognized by
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 shor ...
in the cytoplasm, which couples the upstream and downstream processing events. Pre-miRNA is then further processed by the RNase
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 shor ...
into mature miRNAs in the cell
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
. There also exists an isoform of Drosha that does not contain a nuclear localization signal, which results in the generation of c-Drosha. This variant has been shown to localize to the cell
cytoplasm The cytoplasm describes all the material within a eukaryotic or prokaryotic cell, enclosed by the cell membrane, including the organelles and excluding the nucleus in eukaryotic cells. The material inside the nucleus of a eukaryotic cell a ...
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. Certain miRNAs have been found to deviate from conventional biogenesis pathways and do not necessarily require Drosha or
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 shor ...
, which is because they do not require the processing of pri-miRNA to pre-miRNA. 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 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 shor ...
.


Clinical significance

Drosha and other miRNA processing enzymes may be important in cancer prognosis. Both Drosha and
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 shor ...
can function as
master regulator In genetics, a master regulator gene is a regulator gene at the top of a gene regulation hierarchy, particularly in regulatory pathways related to cell fate and differentiation. Examples Most genes considered master regulators code for transcri ...
s of miRNA processing and have been observed to be down-regulated in some types of
breast cancer Breast cancer is a cancer that develops from breast tissue. Signs of breast cancer may include a Breast lump, lump in the breast, a change in breast shape, dimpling of the skin, Milk-rejection sign, milk rejection, fluid coming from the nipp ...
. The alternative splicing patterns of Drosha in
The Cancer Genome Atlas The Cancer Genome Atlas (TCGA) is a project to catalogue the genomic alterations responsible for cancer using genome sequencing and bioinformatics. The overarching goal was to apply high-throughput genome analysis techniques to improve the abili ...
have also indicated that c-drosha appears to be enriched in various types of breast cancer,
colon cancer Colorectal cancer (CRC), also known as bowel cancer, colon cancer, or rectal cancer, is the development of cancer from the colon or rectum (parts of the large intestine). Signs and symptoms may include blood in the stool, a change in bowel ...
, and
esophageal cancer Esophageal cancer (American English) or oesophageal cancer (British English) is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include dysphagia, difficulty in swallowing and weigh ...
. However, the exact nature of the association between microRNA processing and
tumorigenesis Carcinogenesis, also called oncogenesis or tumorigenesis, is the formation of a cancer, whereby normal cells are transformed into cancer cells. The process is characterized by changes at the cellular, genetic, and epigenetic levels and abn ...
is unclear, but its function can be effectively examined by siRNA knockdown based on an independent validation. 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.


References


Further reading

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External links

* {{PDBe-KB2, Q9NRR4, Ribonuclease 3 Ribonucleases MicroRNA RNA interference RNA-binding proteins