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 double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

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 double-stranded RNA fragments called small interfering RNA and microRNA, respectively. These fragments are approximately 20–25 base pairs long with a two-base overhang on the 3′-end. Dicer facilitates the activation of the RNA-induced silencing complex (RISC), which is essential for RNA interference. RISC has a catalytic component Argonaute, which is an endonuclease capable of degrading messenger RNA (mRNA).

MicroRNAs

RNA interference is a process where the breakdown of RNA molecules into a microRNA (miRNA) inhibits gene expression of specific host mRNA sequences. miRNA is produced within the cell starting from primary miRNA (pri-miRNA) in the nucleus. These long sequences are cleaved into smaller precursor miRNA (pre-miRNA), which are usually 70 nucleotides with a hairpin structure. Pri-miRNA are identified by DGCR8 and cleaved by Drosha to form the pre-miRNA, a process that occurs in the nucleus. These pre-miRNA are then exported to the cytoplasm, where they are cleaved by Dicer to form mature miRNA.

Small Interfering RNAs

Small interfering RNA (siRNA) are produced and function in a similar manner to miRNA by cleaving double-stranded RNA with Dicer into smaller fragments, 21 to 23 nucleotides in length. Both miRNAs and siRNAs activate the RNA-induced silencing complex (RISC), which finds the complementary target mRNA sequence and cleaves the RNA using RNase. This in turn silences the particular gene by RNA interference. siRNAs and miRNAs differ in the fact that siRNAs are typically specific to the mRNA sequence while miRNAs aren't completely complementary to the mRNA sequence. miRNAs can interact with targets that have similar sequences, which inhibits translation of different genes. In general, RNA interference is an essential part of normal processes within organisms such as humans, and it is an area being researched as a diagnostic and therapeutic tool for cancer targets.

Diagnostic and therapeutic applications

Dicer can be used to identify whether tumors are present within the body based on the expression level of the enzyme. A study showed that many patients that had cancer had decreased expression levels of Dicer. The same study showed that lower Dicer expression correlated with lower patient survival length. Along with being a diagnostic tool, Dicer can be used for treating patients by injecting foreign siRNA intravenously to cause gene silencing. The siRNA was shown to be delivered in two ways in mammalian species such as mice. One way would be to directly inject into the system, which would not require Dicer function. Another way would be to introduce it by plasmids that encode for short hairpin RNA, which are cleaved by Dicer into siRNA. One of the advantages of using Dicer to produce siRNA therapeutically would be the specificity and diversity of targets it can affect compared to what is currently being used such as antibodies or small molecular inhibitors. In general, small molecular inhibitors are difficult in terms of specificity along with unendurable side effects. Antibodies are as specific as siRNA, but it is limited by only being able to be used against ligands or surface receptors. On the other hand, low efficiency of intracellular uptake is the main obstacle of injection of siRNA. Injected SiRNA has poor stability in blood and causes stimulations of non-specific immunity. Also, producing miRNA therapeutically lacks in specificity because only 6-8 nucleotide base pairing is required for miRNA to attach to mRNA.

Plant Dicer-like (DCL) proteins

Plant genomes encode Dicer-like proteins with similar functions and protein domains as animal and insect Dicers. For example, in the model organism Arabidopsis thaliana, four Dicer-like-encoding genes have been described and are designated DCL1 to DCL4; there are four Dicer family proteins encoded in a typical eudicot genome. DCL1 is involved with miRNA generation and sRNA production from inverted repeats. DCL2 creates siRNA from cis-acting antisense transcripts which aid in viral immunity and defense. DCL3 generates heterochromatic siRNAs which direct and reinforce DNA methylation and chromatin modifications; DCL4 is involved in trans-acting siRNA metabolism and transcript silencing at the post-transcriptional level. The genomes of most monocots including rice and maize encode a fifth DCL protein, Dicer-like 5 or DCL5. Originally called DCL3b due to its emergence from a monocot-specific duplication of DCL3, DCL5 plays an important role in male reproductive development. The name of DCL5 was originally proposed based on its divergence within rice and conservation in other grasses, which led to the speculation that it had a distinct function.

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