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The DGCR8 microprocessor complex subunit (DiGeorge syndrome chromosomal [or critical] region 8) is a protein that in humans is encoded by the DGCR8 gene.[1] In other animals, particularly the common model organisms Drosophila melanogaster and Caenorhabditis elegans, the protein is known as pasha (partner or Drosha).[2] It is a required component of the RNA interference pathway. ''

1 Function

''DGCR8 is localized to the cell nucleus and is required for microRNA (miRNA) processing. It binds to Drosha, an RNase III enzyme, to form the Microprocessor complex that cleaves a primary transcript known as pri-miRNA to a characteristic stem-loop structure known as a pre-miRNA, which is then further processed to miRNA fragments by the enzyme Dicer. DGCR8 contains an RNA-binding domain and is thought to bind pri-mRNA to stabilize it for processing by Drosha.[3]''

 DiGeorge syndrome critical region gene 8 (DGCR8) is a protein encoded by the DGCR8 gene, which is located in the DiGeorge syndrome critical region of chromosome 22. The DGCR8 protein, commonly called pasha in invertebrates, associates with another protein called Drosha to form a complex known as the microprocessor. The microprocessor is responsible for the nuclear processing of pri-miRNA before it is transported to the cytoplasm for further processing.

Structure
The protein DGCR8 is 773 amino acids in length and contains 14 exons. Its N-terminus contains a WW binding motif, while the C-terminus contains a pair of double stranded RNA binding domains (dsRBD). The dsRBD can only associate with double stranded RNA (dsRNA) but have to undergo major distortion for both domains to be bound at the same time. The two domains have the capacity to bind separately to different dsRNA in pri-miRNA. The dsRBD on the DGCR8 protein ultimately bind to dsRNAs in the pri-miRNA found in the nucleus. When this occurs the dsRNA is cleaved by another protein, Drosha, which associates with DGCR8.

Microprocessor


DGCR8 functions in the nuclear processing of pri-miRNA by associating with its partner Drosha, an RNase III enzyme, to form a multi-protein complex called the microprocessor. The role of DGCR8 in the microprocessor is to bind to the pri-miRNA. This is mediated by the two double stranded RNA binding domains (dsRBD) on DGCR8. Two regions of the pri-miRNA are critical for DGCR8 to recognize and bind to; a ~33bp harpin stem and flanking single stranded RNA (ssRNA) segments. DGCR8 binds to the pri-miRNA at a junction between the ssRNA and dsRNA harpin stem. Once bound it anchors the microprocessor and is used to determine the cleavage site between dsRNA harpin stem and the ssRNA flanking regions. Drosha then cleaves the pri-miRNA 11 base pairs (bp) from the junction between ssRNA and the dsRNA. This produces a 70 nucleotide pre-miRNA with a two nucleotide 3’ overhang. The 3’ overhang is recognized by exportin-5 which transports the pre-miRNA  out of the nucleus for further processing in the cytoplasm.

Regulation
Both elements of the microprocessor regulate each other to maintain a balance between amounts of Drosha and DGCR8. DGCR8 stabilizes Drosha through an interaction between its C-terminal and Drosha’s middle domain. While Drosha post-transcriptionally regulates DGCR8 by cleaving a harpin in DGCR8 mRNA. Specifically, Drosha cleaves two harpins in DGCR8 mRNA. One is located in the 5’ untranslated region (UTR) and the other is in the coding sequencing of DGCR8 mRNA. Cleaving these regions degrades DGCR8 mRNA reducing the amount found in the nucleus. Reduced amounts of DGCR8 negatively regulate the rate of RNA biosynthesis and the processing of pri-miRNA since less DGCR8 is available to interact Drosha to form the microprocessor.

DiGeorge Syndrome
DiGeorge Syndrome is a phenotypically heterogeneous disease caused by a microdeletion in the 22q11.2 chromosome region causing the individual to be hemizygous for this region. Phenotypically, individuals exhibit behavioural and cognitive defects such as impairments in social judgment, motor skills, verbal learning, and executive functioning. MiRNAs are important for brain development and plasticity, however individuals with this deletion display abnormalities in miRNA production in the brain. DGCR8 is implicated in the disease for two main reasons; the DGCR8 gene is found in the 22q11.2 chromosome region and DGCR8 functions in miRNA processing by facilitating the cleaving of pri-miRNA. The 22q11.2 deletion causes the haploinsufficiency of DGCR8, resulting in the reduced processing of miRNA. The change in the abundance of miRNAs have been implicated in deficiencies in synaptic development and maturation.

Schizophrenia
Individuals with the 22q11.2 microdeletion have a 20-25% risk of developing schizophrenia and related psychotic diseases. In normal individuals, the circuitry of the prefrontal cortex (PFC) requires miRNA expression. In schizophrenia patients, the circuitry of the prefrontal cortex (PFC) is altered due to decrease in miRNA expression. The decrease in miRNA expression is caused by the haploinsufficieny of DGCR8 because of the deletion of the 22q11.2 chromosomal region. This is why the 22q11.2 deletion is the strongest genetic risk factor for schizophrenia. The deletion containing DGCR8 accounts for 1-2% of all schizophrenia cases in the population.