Drosha is a Class 2

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 chara ...

enzyme Enzymes () are proteins that act as biological catalysts by accelerating chemical reactions. The molecules upon which enzymes may act are called substrates, and the enzyme converts the substrates into different molecules known as products. ...

that in humans is encoded by the ''DROSHA'' (formerly ''RNASEN'')

gene In biology, the word gene (from , ; "...Wilhelm Johannsen coined the word gene to describe the Mendelian units of heredity..." meaning ''generation'' or ''birth'' or ''gender'') can have several different meanings. The Mendelian gene is a ba ...

. 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 short ...

. It has been found significant in clinical knowledge for cancer prognosisSlack FJ, Weidhaas JB (December 2008). "MicroRNA in cancer prognosis". ''The New England Journal of Medicine.'' 359 (25): 2720-2. and HIV-1 replication.Swaminathan, G., Navas-Martín, S., & Martín-García, J. (2014). MicroRNAs and HIV-1 infection: antiviral activities and beyond. ''Journal of molecular biology'', ''426''(6), 1178-1197.

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

and

Argonaute The Argonaute protein family, first discovered for its evolutionarily conserved stem cell function, plays a central role in RNA silencing processes as essential components of the RNA-induced silencing complex (RISC). RISC is responsible for the ...

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 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 carbohydra ...

-specific

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 ...

s participate in diverse

maturation and decay pathways in

eukaryotic 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. Bact ...

and

prokaryotic A prokaryote () is a single-celled organism that lacks a nucleus and other membrane-bound organelles. The word ''prokaryote'' comes from the Greek πρό (, 'before') and κάρυον (, 'nut' or 'kernel').Campbell, N. "Biology:Concepts & Connec ...

cells. The RNase III Drosha is the core

nuclease A nuclease (also archaically known as nucleodepolymerase or polynucleotidase) is an enzyme capable of cleaving the phosphodiester bonds between nucleotides of nucleic acids. Nucleases variously effect single and double stranded breaks in their ...

that executes the initiation step of

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) processing in the

nucleus Nucleus ( : nuclei) is a Latin word for the seed inside a fruit. It most often refers to: *Atomic nucleus, the very dense central region of an atom *Cell nucleus, a central organelle of a eukaryotic cell, containing most of the cell's DNA Nucle ...

. The microRNAs thus generated are short

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 A complement is something that completes something else. Complement may refer specifically to: The arts * Complement (music), an interval that, when added to another, spans an octave ** Aggregate complementation, the separation of pitch-class ...

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 o ...

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 mRNAs ...

s known as a ''pri-miRNAs'', which are cleaved by Drosha to produce a characteristic

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 ...

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 multienzyme complexes, in which multiple catalytic domains are found in a single polypeptide chain. Protein ...

called the

Microprocessor complex The microprocessor complex is a protein complex involved in the early stages of processing microRNA (miRNA) and RNA interference (RNAi) in animal cells. The complex is minimally composed of the ribonuclease enzyme Drosha and the dimeric RNA-bi ...

, which also contains the double-stranded RNA binding protein

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 ele ...

(called

Pasha Pasha, Pacha or Paşa ( ota, پاشا; tr, paşa; sq, Pashë; ar, باشا), in older works sometimes anglicized as bashaw, was a higher rank in the Ottoman political and military system, typically granted to governors, generals, dignitari ...

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 RNA-binding protein EWS is a protein that in humans is encoded by the ''EWSR1'' gene on human chromosome 22, specifically 22q12.2. It is one of 3 proteins in the FET protein family. The q22.2 region of chromosome 22 encodes the N-terminal transa ...

, FUS,

hnRNPs 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 ...

, p68, and p72. Both Drosha and DGCR8 are localized to 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 ...

, 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

in the cytoplasm, which couples the upstream and downstream processing events. Pre-miRNA is then further processed by the RNase

into mature miRNAs in the cell

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. Th ...

. 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

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

, which is because they do not require the processing of pri-miRNA to pre-miRNA.Suzuki, H. I., & Miyazono, K. (2011). Emerging complexity of microRNA generation cascades. ''The Journal of Biochemistry'', ''149''(1), 15-25. 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

Clinical significance

Drosha and other miRNA processing enzymes may be important in cancer prognosis. Both Drosha and

can function as

master regulator In genetics, a master regulator is a 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 transcription factor pr ...

s of miRNA processing and have been observed to be down-regulated in some types of

breast cancer Breast cancer is cancer that develops from breast tissue. Signs of breast cancer may include a lump in the breast, a change in breast shape, dimpling of the skin, milk rejection, fluid coming from the nipple, a newly inverted nipple, or a r ...

. The alternative splicing patterns of Drosha in

The Cancer Genome Atlas ''The'' () is a grammatical article in English, denoting persons or things already mentioned, under discussion, implied or otherwise presumed familiar to listeners, readers, or speakers. It is the definite article in English. ''The'' is the ...

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 m ...

, and

esophageal cancer Esophageal cancer is cancer arising from the esophagus—the food pipe that runs between the throat and the stomach. Symptoms often include difficulty in swallowing and weight loss. Other symptoms may include pain when swallowing, a hoarse voic ...

. 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 abnor ...

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

External links

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

History

Function

Clinical significance

References

Further reading

External links