DICER1: The Argonaute Endonuclease Family Member and Its Role in Pediatric and Youth Pathology

Abstract

In 2001, two enzyme-encoding genes were recognized in the fruit fly Drosophila melanogaster. The genetic material, labeled Dicer-1 and Dicer-2, encodes ribonuclease-type enzymes with slightly diverse target substrates. The human orthologue is DICER1. It is a gene, which has been positioned on chromosome 14q32.13. It contains 27 exons, which are linking the two enzyme domains. DICER1 is found in all organ systems. It has been proved that it is paramount in human development. The protein determined by DICER1 is a ribonuclease (RNase). This RNase belongs to the RNase III superfamily, formally known as 'endoribonuclease'. It has been determined that the function of RNase III proteins is set to identify and degrade double-stranded molecules of RNA. DICER1 is a vital "housekeeping" gene. The multi-domain enzyme is key for small RNA processing. This enzyme functions in numerous pathways, including RNA interference paths, DNA damage renovation, and response to viruses. At the protein level, DICER is also involved in several human diseases, of which the pleuro-pulmonary blastoma is probably the most egregious entity. Numerous studies have determined the full range of DICER1 functions and the corresponding relationship to tumorigenic and non-neoplastic diseases. In fact, genetic mutations (somatic and germline) have been detected in DICER1 and are genetically associated with at least two clinical syndromes: DICER1 syndrome and GLOW syndrome. The ubiquity of this enzyme in the human body makes it an exquisite target for nanotechnology-supported therapies and repurposing drug approaches.

Keywords: DICER1; biology; molecular genetics; oncogene.

Figure 1

RNAi. RNA interference (RNAi), also known as PTGS or Post-Transcriptional Gene Silencing (PTGS) or Genetic Perturbation Platform, is a preserved biological mechanism that responds to dsRNA or double-stranded RNA, enabling resistance to both parasite of endogenous origin and exogenous harmful nucleic acids, while regulating the expression of genes, which codify proteins. This innate process for sequence-explicit gene silencing has the potential to transform experimental biology. It may have significant applications in genomics and functional genomics, as well as therapeutic intervention and other fields. Endogenous activators of the RNAi path including foreign DNA or dsRNA of viral origin, inconsistent transcripts from repeating genomic sequences (e.g., transposons), and pre-miRNA (miRNA, microRNA). In plants, RNAi underpins virus-induced gene silencing (VIGS), indicating a significant role in disease resistance. Investigations on C. elegans (Caenorhabditis elegans) has proposed a potential method for the control of endogenous genes by the RNAi machinery. In mammalian cells, large double-stranded RNAs (>30 nt) typically elicit an interferon response. A streamlined model for the RNAi process consists of two stages. Both stages involve a ribonuclease enzyme. The first step is for the RNase II enzymes Dicer and Drosha to transform the trigger RNA (which could be dsRNA or miRNA primary transcript) into short interference RNA (siRNA). The RNA-induced silencing complex (RISC) is an effector complex that incorporates siRNAs in the following step. As the RISC is assembled, the siRNA is unwound, allowing the single-stranded RNA to hybridize with the mRNA target. Argonaute, an RNase H enzyme, destroys the target mRNA, resulting in gene silencing (Slicer). The messenger RNA stays uncleaved if the siRNA/mRNA duplex displays mismatches. When translational inhibition occurs, genes are silenced. This illustration depicting RNA interference was adapted from the NCBI website: RNA Interference (RNAi) [4,5,6,7,8,9]. Functional studies of the mammalian genome can show how genetic changes cause changes in phenotype, and the Genetic Perturbation Platform (GPP), formerly known as the RNA interference (RNAi) Platform, supports these investigations.

Figure 2

Various dsRNA. Schematic depiction of the characteristics and origins of various dsRNA substrates. There are two possible sources for genomic transcripts that produce double-stranded RNA (dsRNA): repeated transcripts in pathways that maintain genome integrity and genetic sequences in pathways that control gene expression (adapted from an Open Access source: Zapletal D, Kubicek K, Svoboda P, Stefl R. Dicer structure and function: conserved and evolving features. EMBO Rep. 2023 Jul 5;24(7):e57215. doi:10.15252/embr.202357215. Epub 2023 Jun 13. PMID: 37310138; PMCID: PMC10328071) [3].

Figure 3

Substrate Cleaning. There are two ways to clean the substrate. During its processive mode, Dicer “feeds” its substrate by slicing lengthy dsRNA molecules in a series of sequential steps that are powered by the helicase domain’s ATP activity. Dicer attaches a new substrate after performing a single cleavage when in distributive mode (adapted from an Open Access source: Zapletal D, Kubicek K, Svoboda P, Stefl R. Dicer structure and function: conserved and evolving features. EMBO Rep. 2023 Jul 5;24(7):e57215. doi:10.15252/embr.202357215. Epub 2023 Jun 13. PMID: 37310138; PMCID: PMC10328071) [3].

Figure 4

CT Imaging and Macroscopic View of Pleuropulmonary Blastoma. (a) CT scan of a 21-year-old female patient with a pleuropulomonary blastoma causing a mediastinal shift (arrow pointing to the mediastinal shift). (b) The figure shows the resected pleuropulmonary blastoma (arrow pointing to the bulk of the tumor) just after surgery. No copyright issue. The images come from the personal archive of Dr. F. Minervini.

Figure 5

Microphotographs of Pleuropulmonary Blastoma. A heterogeneous solid tumor (a) abutting (arrow) the fibrotic pleura showing on higher magnification blastema-like area (arrow) infiltrating the soft tissue and exhibiting small-to-medium sized cells to very large cells (round, ovoid, slightly spindle) with hyperchromatic nuclei, high nucleus to cytoplasm ratio, and frequent mitotic bodies (b). In this case, foci of very large anaplastic cells (red arrow) with pleomorphic nuclei and mitotic figures as well as apoptotic figures (black arrow) were also observed (figure and inset). Hematoxylin and eosin staining, scale bar embedded in the microphotographs. No copyright issue. The images come from the personal archive of Dr. C. Sergi.

Figure 6

DICER1 associated lung cysts (arrows) in an asymptomatic 22-year-old male patient. No copyright issue. The image comes from the personal archive of Dr. F. Minervini.