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MicroRNA Processing by Dicer
MicroRNAs (miRNAs) are small non-coding RNAs that are about 22 nucleotides in length. They regulate gene expression post-transcriptionally with the effector protein complex, containing Argonaute or trinucleotide repeat containing 6 (TNRC6) proteins, and target mRNAs in a sequence-dependent manner, causing the translational repression and destabilization of the target mRNAs. Both Drosha and Dicer, members of the RNase III family proteins, are essential components in the canonical miRNA biogenesis pathway. miRNA is transcribed into primary-miRNA (pri-miRNA) from genomic DNA. Drosha then cleaves the flanking regions of pri-miRNA into precursor-miRNA (pre-miRNA), while Dicer cleaves the loop region of the pre-miRNA to form a miRNA duplex. In this report, we summarized and discussed the current reports in which double-stranded RNA binding proteins (dsRBPs), such as TAR RNA binding protein (TRBP) or the adenosine deaminase acting on RNA (ADAR), modulate the processing of miRNA by Dicer in various manners.
MicroRNAs (miRNAs) are single-stranded RNAs of approximately 22 nucleotides in length and are classified as small non-coding RNAs. The miRNAs regulate gene expression post-transcriptionally by a mechanism known as RNA silencing, where miRNA is loaded onto Argonaute (AGO), a core component of the miRNA-induced silencing complex (miRISC) . While on AGO, the miRNA recognizes target mRNAs that have sequences that are complementary to the “seed region” (positions 2–8 from the 5′ end) of the miRNA in their 3′ untranslated region . As the seed region only consists of seven nucleotides, each miRNA is capable of recognizing and regulating many types of mRNAs, indicating that miRNA–mRNA gene expression networks are highly complicated.
Some of the miRNAs that have been discovered in diverse eukaryotes are evolutionally conserved, while others are species specific . The first two miRNAs, lin-4 and let-7, were discovered in Caenorhabditis elegans ( C. elegans ) through the analysis of the heterochronic gene mutants that undergo development/differentiation at an abnormal time within the organism . Let-7 is evolutionally conserved across various species, including in humans. In human lung cancer cells, let-7 regulates cell proliferation and also suppresses the expression levels of NRAS and KRAS, two genes that induce oncogenic transformation when mutated . Thus, although let-7 is conserved in both C. elegans and humans, its function in the two species is different.
At the initial stage of miRNA biogenesis, miRNA is transcribed by RNA polymerase II (Pol II) as primary-miRNA (pri-miRNA) , which has stem loop structures  (Figure 1). In the canonical miRNA biogenesis pathway, the flanking regions of the pri-miRNA are cleaved to generate precursor-miRNA (pre-miRNA) in the nucleus by a microprocessor complex consisting of Drosha, a member of the RNase III family proteins, and its cofactor DiGeorge syndrome critical region 8 (DGCR8), a double-stranded RNA (dsRNA) binding protein (dsRBP) . The pre-miRNA is transported from the nucleus to the cytoplasm by Exportin-5 (EXP5), which then couples with GTP-bound Ran . In the cytoplasm, Dicer, an RNase III family protein, cleaves off the loop region of the pre-miRNA to generate a miRNA duplex in collaboration with the trans-activation response (TAR) RNA binding protein (TRBP) in the canonical miRNA biogenesis pathway . The interaction of the Dicer–TRBP complex with Argonaute (AGO) facilitates the loading of the miRNA duplex onto AGO to form the RISC-loading complex (RLC) . The miRNA duplex is then unwound into single stranded miRNAs; the RNA strand that remains on the AGO protein acts as the miRNA, while the other strand is discarded . The former is called the guide strand, and the latter is called the passenger strand. The mature miRNA on the AGO protein guides the RISC to target mRNAs that have sequences that are complementary to the seed region of the miRNA. After binding to the mRNA, AGO recruits the trinucleotide repeat containing 6 (TNRC6) protein, a scaffold protein tethering effector proteins to destabilize and translationally repress target mRNAs by inducing their decapping and deadenylation .
Figure 1. Overview of miRNA biogenesis and the RNA silencing pathway. Pri-miRNAs are transcribed from the genome by Pol II. In the nucleus, pri-miRNA is cleaved by a microprocessor complex consisting of Drosha and DGCR8 to produce pre-miRNA, which is then transported from the nucleus to the cytoplasm by EXP5 coupled with GTP-bound Ran (RanGTP). Cleavage of pre-miRNA is performed by Dicer and its cofactor, TRBP, in a canonical miRNA biogenesis pathway. After pre-miRNA cleavage, the miRNA duplex is loaded onto AGO proteins through formation of the RLC complex. The mature miRNA guides the RISC complex to target mRNAs that are complementary to the seed region of miRNA. Recruitment of the TNRC6 protein induces the destabilization and translational repression of the target mRNA.
2. Processing of Pre-miRNA by Dicer
3. Enhancement of Pre-miRNA Processing by Dicer via TRBP/PACT
Dicer-associated proteins regulate the substrate recruitment and the cleavage activity of Dicer . The processing of pre-miRNA is not only promoted by TRBP but also by other Dicer-associated proteins, such as PACT, a protein activator of protein kinase R (PKR) . TRBP is a protein that binds to TAR RNA, a hairpin-structured RNA that is encoded by human immunodeficiency virus type I . PACT is a protein that was initially identified as an activator of PKR . TRBP and PACT have highly conserved domain structures with three dsRBDs  (Figure 2a). The dsRBDs are divided into two subclasses, type-A and type-B. Type-A has a conserved αβββα motif with a high affinity to dsRNA . Type-B, also termed half dsRBD, has poorly conserved N-terminal sequences in the αβββα motif and is associated with protein–protein interactions . The first and second dsRBDs of TRBP and PACT are type-As, and the third dsRBD is a type-B that binds to Dicer through the DExD/H-box helicase domain .
Both TRBP and PACT interact with Dicer to promote the cleavage of the pre-miRNA in the RLC containing AGO protein and the facilitate loading of the miRNA duplex onto AGO . It was reported that deletion or mutation of the DExD/H-box helicase domain of Dicer activated the cleavage of its substrates, which suggested that this domain inhibits catalytic activity rather than affecting RNA-substrate binding . TRBP binds to the DExD/H-box helicase domain of Dicer and stimulates the cleavage activity of Dicer. Therefore, the DExD/H-box helicase domain functions as an intramolecular structural switch that maintains Dicer in a low-activity state until the partner proteins interact with its DExD/H-box helicase domain. In addition, it was reported that TRBP facilitates the processing activity of pre-miRNA by Dicer in RNA-crowded molecular environments  and that it also facilitates the recruitment of pre-miRNAs to the PAZ domain of Dicer. Furthermore, the sliding motion of TRBP on dsRNA with Dicer has been reported . This was associated with the higher substrate cleavage activity of Dicer compared to Dicer alone, which suggests that TRBP facilitates the cleavage activity of Dicer by guiding Dicer to the substrates. To date, no studies on the mechanism by which PACT promotes Dicer-mediated cleavage of pre-miRNAs have been reported. However, the amino acid sequence of the Dicer-interacting dsRBD of PACT was found to be similar to that of TRBP. It has yet to be determined if PACT interacts with Dicer by a mechanism similar to that of TRBP and if it enhances the processing of similar types of pre-miRNAs.
TRBP and PACT have different functions. Although TRBP preferentially binds to simple duplex RNA, PACT inhibits Dicer-mediated dsRNA cleavage for siRNA production . Unlike PACT, the cleavage site for Dicer-TRBP shifts when compared to cleavage by Dicer alone . PACT and TRBP have no redundant effects on the production of isomiRs , different-sized miRNAs that alter the downstream target-binding specificities. Such differences in dsRNA recognition and processing behavior are attributed to two N-terminal RNA-binding domains in each protein.
Several studies have addressed the TRBP-mediated maturation of specific miRNAs and its effect on downstream pathways. It was reported that the TRBP-mediated maturation of miR-208a decreased the expression level of SRY-Box Transcription Factor 6 (Sox6), which is required for normal heart function . It was also reported that disruptions of TRBP-dependent maturations of tumor suppressor certain miRNAs (TS-miRs), miR-143 and miR-145, were related to the self-renewal and tumor maintenance of cancer stem cells . These results suggest that TRBP regulates biogenesis and the downstream gene regulatory pathways of specific miRNAs.
4. Enhancement of Pre-miRNA Processing by Dicer via ADAR1
5. TRBP-LGP2 Interaction Inhibits Pre-miRNA Processing by Dicer
In virus infected mammalian cells, virus-derived RNAs are captured by viral sensor proteins such as retinoic acid-inducible gene I-like receptors (RLRs), inducing the production of type I interferon . Recently, we reported that the TRBP-mediated maturations of pre-miRNAs were inhibited through the competitive binding of the laboratory of genetics and physiology 2 (LGP2) to Dicer–TRBP interaction during Sendai virus infection . Interferons enhanced the expression of LGP2, which interacted with TRBP to inhibit the Dicer–TRBP interaction . Following LGP2-dependent inhibition of Dicer–TRBP interaction, the maturations of TRBP-bound pre-miRNAs, including miR-106b, were suppressed. The inhibition of the maturation of such miRNAs increased the expression of apoptosis-related genes downstream of miRNA processing. This finding suggested that the crosstalk between antiviral response and miRNA biogenesis is regulated by TRBP binding to the specific pre-miRNAs.
This entry is adapted from 10.3390/ncrna7030057
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