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Pleuropulmonary Blastoma
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
Raúl Barrera-Rodríguez, Carlos Pérez-Malagón
Using a family-based linkage study in four families with inherited predisposition to PPB, Hill et al. in 2009 [10] mapped the PPB locus to chromosome 14q31.1-q32 in a region of 7-Mb flanked by rs12886750 and rs8008246. Then, by gene sequence analysis, it was demonstrated that germline mutations in DICER1 gene (OMIM, 601200; NCBI Gene 23405) are associated with susceptibility to familial PPB. The gene encodes a ∼218 kDa cytoplasmic endonuclease that belongs to the ribonuclease III (RNase IIIb; PDB Structure, 2EB1) protein family, which is required to cleave the precursor microRNAs (pre-miRNAs) into ∼22 nucleotide “mature” effector miRNAs and small interfering RNAs (siRNAs), both are the crucial modulators of gene expression at the post-transcriptional level [15–17]. The miRNAs negatively regulate gene expression and appear to play critical roles in stem cell proliferation, organogenesis, cell cycle progression, regulatory control of some lymphocyte subsets, and oncogenesis (Figure 6.1) [14,18].
RNA
Published in Paul Pumpens, Single-Stranded RNA Phages, 2020
The spatial organization of the MS2 RNA was studied at that time in Moscow. Thus, the exposed sites for single-strand- and double-strand-specific nucleases were identified by limited hydrolysis with nuclease S1 and double-strand-specific snake venom ribonuclease (Grechko et al. 1982). Next, this study was expanded with the double-strand-specific ribonuclease III treatment (Grechko et al. 1985b). The ribonuclease III was an E. coli nuclease specific for double-stranded RNA (Robertson et al. 1967). The restoration of the three-dimensional structure of the MS2 RNA was evaluated after heating above the melting point (Grechko et al. 1985a) and the accessibility to the S1 and snake venom nucleases was combined by evaluation with thermal stability of the MS2 RNA (Grechko et al. 1987). Fluorescent dyes were involved in these studies on the secondary structure of the MS2 RNA, where the interaction of ethidium bromide with double-stranded, and acridine orange with single-stranded fragments was evaluated in a wide range of ionic strength, ion compositions, and at various pH (Borisova et al. 1984a,b, 1987).
Non-coding RNAs – A primer for the laboratory scientist
Published in British Journal of Biomedical Science, 2019
The initial synthesis of an miRNA transcript by a polymerase generates a pri-miRNA molecule which in secondary structure has a hairpin shape. 5ʹ and 3ʹ tails are trimmed within the nucleus by Drosha, a ribonuclease III, yielding a ~ 60 nucleotide pre-miRNA that translocates to the cytoplasm and binds with Dicer, an endonuclease that dissociates the secondary structure. One of the single stands, in conjunction with a protein called Argonaute, forms an RNA-induced silencing complex (RISC). The single strand miRNA binds to its target mRNA within the RISC, resulting in the degradation of the message [5,11,12] (Figure 1). Genes coding for miRNAs may be found by themselves, or in polycistron clusters that together may contain >33% of the total miRNA pool [13]. One cluster, that of miR-17-92 at 13q31-q3, produces seven mature miRNAs: miR-17-3p, miR-17-5p, miR-18a, miR-19a, miR-19b, miR-20a, and 92a. More than 30 downstream targets of these miRNAs have been reported in – stroke, heart disease, bone development and in cancer. The ever-expanding field of miRNA forces us to focus on only a few areas of pathology.
From pathogenesis to novel therapies in primary hyperoxaluria
Published in Expert Opinion on Orphan Drugs, 2019
Gill Rumsby, Sally-Anne Hulton
RNA interference (RNAi) is a natural means of silencing gene expression (for a review see [77]. It is initiated in vivo by double stranded RNA (dsRNA) that is sliced into smaller fragments of 21 nucleotides in length by ribonuclease III cleavage to form small interfering RNAs (siRNA) that can suppress expression of specific genes. Larger fragments >30 bp may also be produced that have non-specific effects including shut down of all gene expression and induction of interferon. The siRNA can be synthesised in vitro to be homologous to the target gene and, on interacting with the mRNA, induces Argonaute 2-mediated degradation. The siRNA molecules can be modified to aid cellular uptake, for example, hepatic uptake is promoted by conjugation with N acetyl galactose (GalNAc) sugar that, on interaction with the asialoglycoprotein receptor, is endocytosed into the hepatocyte. This modification allows intravenous or subcutaneous administration of the molecule. The potential side effects of this treatment are improper target recognition and delivery induced toxicity.
The application of gene silencing in proteomics: from laboratory to clinic
Published in Expert Review of Proteomics, 2018
Maura Brioschi, Cristina Banfi
Inside the cells, dsRNAs, derived from transposons or replicating viral vectors, and miRNAs are processed into short dsRNAs able to activate the cytoplasmic ribonuclease III-like protein Dicer, which cleaved them into small RNA duplexes of 19–25 bp with 3′-dinucleotide overhangs. After that, these small interfering RNAs, siRNAs, interact with a multiprotein complex known as RNA-induced silencing complex (RISC) in which an ATP-dependent helicase generates two independent oligonucleotides strands [4]. The single-strand antisense siRNA recognizes the target mRNA and aligns the RISC complex with the specific mRNA region, while the catalytic protein of the RISC complex, Argonaute 2, cleaves mRNA (Figure 1(a)) [24,25].