Drosha

DROSHA
Available structures PDB Ortholog search: PDBe RCSB List of PDB id codes 2KHX, 5B16
Identifiers
Aliases	DROSHA, ETOHI2, HSA242976, RANSE3L, RN3, RNASE3L, RNASEN, drosha ribonuclease III
External IDs	OMIM: 608828; MGI: 1261425; HomoloGene: 8293; GeneCards: DROSHA; OMA:DROSHA - orthologs
Gene location (Human) Chr. Chromosome 5 (human)[1] Band 5p13.3 Start 31,400,494 bp[1] End 31,532,196 bp[1]
Gene location (Mouse) Chr. Chromosome 15 (mouse)[2] Band 15|15 A1 Start 12,824,901 bp[2] End 12,935,377 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in endothelial cell ventricular zone germinal epithelium Brodmann area 23 right hemisphere of cerebellum ganglionic eminence middle temporal gyrus sural nerve epithelium of colon anterior pituitary Top expressed in primitive streak Paneth cell otolith organ fossa utricle condyle substantia nigra Rostral migratory stream aortic valve ascending aorta More reference expression data BioGPS More reference expression data
Gene ontology Molecular function ribonuclease III activity protein homodimerization activity lipopolysaccharide binding metal ion binding endoribonuclease activity protein binding nuclease activity endonuclease activity hydrolase activity RNA binding DEAD/H-box RNA helicase binding SMAD binding R-SMAD binding primary miRNA binding double-stranded RNA binding Cellular component nucleoplasm microprocessor complex nucleolus nucleus plasma membrane focal adhesion postsynaptic density Biological process RNA processing ribosome biogenesis nucleic acid phosphodiester bond hydrolysis rRNA catabolic process positive regulation of gene expression defense response to Gram-negative bacterium regulation of miRNA metabolic process primary miRNA processing regulation of gene expression defense response to Gram-positive bacterium RNA phosphodiester bond hydrolysis, endonucleolytic regulation of regulatory T cell differentiation RNA phosphodiester bond hydrolysis regulation of inflammatory response miRNA metabolic process gene silencing production of siRNA involved in RNA interference pre-miRNA processing Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 29102 14000 Ensembl ENSG00000113360 ENSMUSG00000022191 UniProt Q9NRR4 Q5HZJ0 RefSeq (mRNA) NM_001100412 NM_013235 NM_001382508 NM_001130149 NM_026799 RefSeq (protein) NP_001093882 NP_037367 NP_001369437 NP_001123621 NP_081075 Location (UCSC) Chr 5: 31.4 – 31.53 Mb Chr 15: 12.82 – 12.94 Mb PubMed search [3] [4]
Wikidata
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Drosha is a Class 2 ribonuclease III enzyme^[5] that in humans is encoded by the DROSHA (formerly RNASEN) gene.^[6][7][8] 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. It has been found significant in clinical knowledge for cancer prognosis.^[9] and HIV-1 replication.^[10]

Human Drosha was cloned in 2000 when it was identified as a nuclear dsRNA ribonuclease involved in the processing of ribosomal RNA precursors.^[11] The other two human enzymes that participate in the processing and activity of miRNA are the Dicer and Argonaute proteins. Recently, proteins like Drosha have been found significant in cancer prognosis^[9] and HIV-1 replication.^[10]

Members of the ribonuclease III superfamily of double-stranded (ds) RNA-specific endoribonucleases participate in diverse RNA maturation and decay pathways in eukaryotic and prokaryotic cells.^[12] The RNase III Drosha is the core nuclease that executes the initiation step of microRNA (miRNA) processing in the nucleus.^[8][11]

The microRNAs thus generated are short RNA molecules that regulate a wide variety of other genes by interacting with the RNA-induced silencing complex (RISC) to induce cleavage of complementary messenger RNA (mRNA) as part of the RNA interference pathway. MicroRNA molecules are synthesized as long RNA primary transcripts known as a pri-miRNAs, which are cleaved by Drosha to produce a characteristic stem-loop structure of about 70 base pairs long, known as a pre-miRNA.^[11] Pre-miRNAs, when associated with EXP5, are stabilized due to removal of the 5' cap and 3' poly(A) tail.^[13]</ref> Drosha exists as part of a protein complex called the Microprocessor complex, which also contains the double-stranded RNA binding protein DGCR8 (called Pasha in D. melanogaster and C. elegans).^[14] DGCR8 is essential for Drosha activity and is capable of binding single-stranded fragments of the pri-miRNA that are required for proper processing.^[15] The Drosha complex also contains several auxiliary factors such as EWSR1, FUS, hnRNPs, p68, and p72.^[16]

Both Drosha and DGCR8 are localized to the cell nucleus, where processing of pri-miRNA to pre-miRNA occurs. These two proteins homeostatically control miRNA biogenesis by an auto-feedback loop.^[16] A 2nt 3' overhang is generated by Drosha in the nucleus recognized by Dicer in the cytoplasm, which couples the upstream and downstream processing events. Pre-miRNA is then further processed by the RNase Dicer into mature miRNAs in the cell cytoplasm.^[11][16] There also exists an isoform of Drosha that does not contain a nuclear localization signal, which results in the generation of c-Drosha.^[17][18] This variant has been shown to localize to the cell cytoplasm 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.^[19]

Certain miRNAs have been found to deviate from conventional biogenesis pathways and do not necessarily require Drosha or Dicer, which is because they do not require the processing of pri-miRNA to pre-miRNA.^[16] 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.^[10]

Drosha and other miRNA processing enzymes may be important in cancer prognosis.^[9] Both Drosha and Dicer can function as master regulators of miRNA processing and have been observed to be down-regulated in some types of breast cancer.^[20] The alternative splicing patterns of Drosha in The Cancer Genome Atlas have also indicated that c-drosha appears to be enriched in various types of breast cancer, colon cancer, and esophageal cancer.^[18] However, the exact nature of the association between microRNA processing and tumorigenesis is unclear,^[21] but its function can be effectively examined by siRNA knockdown based on an independent validation.^[22]

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.^[10]

• Overview of all the structural information available in the PDB for UniProt: Q9NRR4 (Ribonuclease 3) at the PDBe-KB.