Cellular functions of the microprocessor

Abstract

The microprocessor is a complex comprising the RNase III enzyme Drosha and the double-stranded RNA-binding protein DGCR8 (DiGeorge syndrome critical region 8 gene) that catalyses the nuclear step of miRNA (microRNA) biogenesis. DGCR8 recognizes the RNA substrate, whereas Drosha functions as an endonuclease. Recent global analyses of microprocessor and Dicer proteins have suggested novel functions for these components independent of their role in miRNA biogenesis. A HITS-CLIP (high-throughput sequencing of RNA isolated by cross-linking immunoprecipitation) experiment designed to identify novel substrates of the microprocessor revealed that this complex binds and regulates a large variety of cellular RNAs. The microprocessor-mediated cleavage of several classes of RNAs not only regulates transcript levels, but also modulates alternative splicing events, independently of miRNA function. Importantly, DGCR8 can also associate with other nucleases, suggesting the existence of alternative DGCR8 complexes that may regulate the fate of a subset of cellular RNAs. The aim of the present review is to provide an overview of the diverse functional roles of the microprocessor.

A novel role for GSK3β as a modulator of Drosha microprocessor activity and MicroRNA biogenesis

“…The pri-miR is cleaved into one or more ∼70 nt hairpin-structured precursor miRs (pre-miRs), by the Drosha-containing Microprocessor (MP) complex (6). Drosha, an RNase III enzyme, is stabilised by association with double-stranded RNA binding domain protein DiGeorge Critical Region 8 (DGCR8)/Partner of Drosha (Pasha) (7). Other cofactors such as p72, p68, FUS and hnRNPA1 modulate fidelity, efficiency and specificity of cleavage or act as scaffold proteins to aid complex formation (8).…”

Targeting RNA for processing or destruction by the eukaryotic RNA exosome and its cofactors

“…DGCR8 contains dsRNA-binding and heme domains, which interact with the stem and apical regions of the pri-miRNA, respectively, as a dimer (Nguyen et al 2015b). In the nucleoplasm, this dimer interacts with DROSHA, an RNA endonuclease involved in miRNA maturation, to ensure its fidelity in producing miRNAs (for review, see Macias et al 2013). Investigators found that DGCR8 also interacts in a distinct complex with the nucleolar exosome, and this interaction is necessary for the turnover of snoRNAs and hTR in that compartment (Macias et al 2015).…”

Roles for miRNAs in endocrine resistance in breast cancer

“…DGR8 anchors and recognizes the miRNA region for endonuclease cleavage by Drosha (Fukunaga, et al 2012; Kim, et al 2009). The Drosha microprocessor complex is also implicated in miRNA-independent functions including regulation of heteronuclear ribonucleoproteins (hnRNPs) and alternative splicing (Macias, et al 2013). Pre-miRNA is exported from the nucleus by Exportin 5 (a RanGTP-dependent dsRNA-binding protein (Bohnsack, et al 2004)) to the cytoplasm where it is further processed by another RNase III enzyme, DICER, in conjugation with trans-activation response (TAR) RNA binding protein (TRBP) and protein activator of the interferon-induced protein kinase (PACT; also known as PRKRA) results in a small dsRNA duplex (~22 nt) (Chendrimada, et al 2005; Kim et al 2009).…”