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Herpesvirus microRNAs for Use in Gene Therapy Immune-Evasion Strategies
Published in Yashwant Pathak, Gene Delivery, 2022
Vineet Mahajan, Shruti Saptarshi, Yashwant Pathak
The degree of sequence complementarity between the miRNA and its target mRNA and the associated Argonaute protein determine the stability of an miRNA.4 Short, single-stranded RNA/DNA molecules called as antisense oligonucleotides (ASOs), antagomirs or blockmirs have been shown to inhibit specific miRNAs in mammalian cells.13 These are chemically engineered antagonists of miRNAs and have therapeutic implications. miRNAs can be cleaved by small RNA degrading nucleases, exoribonuclease, and other endo and exonuclease. miRNA sponges are plasmid or viral vectors containing tandemly arrayed miRNA binding sites; separated with a small nucleotide spacer, they can inhibit an entire family of miRNA by using the common seed sequence, and can therefore inhibit multiple miRNAs at once.14
Perlman Syndrome
Published in Dongyou Liu, Handbook of Tumor Syndromes, 2020
The DIS3L2 gene (a mammalian exosome-independent homolog of Schizosaccharomyces pombe yeast Dis3 gene) on chromosome 2q37.1 spans 383 kb and generates five splice variants, the longest of which encodes a 885 aa, 99.2 kDa protein (DIS3L2). Constituting a member of the highly conserved RNaseII/RNB family of 3′–5′ exoribonucleases, DIS3L2 demonstrates 3′/5′ exoribonucleolytic activity, which is critical for degradation of both mRNA and non-coding RNA. Specifically, 3′−5′ exoribonuclease recognizes mRNA and miRNA that are polyuridylated at the 3′ end by terminal uridylyltransferase and mediates their degradation. This RNA degradation pathway plays a vital role in the regulation of mitosis and cell proliferation [5,6].
Transport of mRNA into the Cytoplasm
Published in Alvaro Macieira-Coelho, Molecular Basis of Aging, 2017
Werner E. G. Müller, Paul S. Agutter, Heinz C. Schröder
The synthesis of the 3′-terminal poly (A) segment of hnRNA and mRNA is catalyzed by poly(A) polymerases (EC 2.7.7.19).93,94 Poly(A) degradation is catalyzed by two enzymes: endoribonuclease IV (EC 3.1.26.6)95 and poly(A)-specific 2′,3′-exoribonuclease (EC 3.1.13.4).96 The activities of these enzymes can be modulated by phosphorylation97 or interaction with cytoskeletal protein.98 Age-dependence studies on quail oviduct revealed that the activity of 2′,3′-exoribonuclease in old animals is three- to fourfold higher than in mature animals.99 On the other hand, the changes in activities of poly(A) polymerase and endoribonuclease IV in the course of aging were found to be negligible. The conclusion drawn from these data, that the poIy(A) segment of mRNA is shorter in senescent animals compared to adult ones, is supported by analytical results.100 Determinations of the sizes of the poly (A) sequences of mRNAs from oviducts of mature and old quails revealed that the length of the poly(A) segment is shortened from an average value of 130 AMP units (adult animal group) to an average value of 70 AMP units (senescent animal group) (Figure 5A); similar results were obtained for liver and heart (Figure 5B and C). Further, the relative amounts of low-molecular-weight oligo(A) fragments formed in vivo in oviducts of mature and old animals have been shown to gradually decrease with aging of the animals;101 the percentage of oIigo(A)2-6 sequences in the mature animal group was found to be six times higher than that of the old animal group. This result may be explained by the fact that due to the higher activity of poly(A) exoribonuclease, oligo(A) fragments, once formed, are rapidly degraded in organs of older animals.
A comprehensive update of siRNA delivery design strategies for targeted and effective gene silencing in gene therapy and other applications
Published in Expert Opinion on Drug Discovery, 2023
Ahmed Khaled Abosalha, Waqar Ahmad, Jacqueline Boyajian, Paromita Islam, Merry Ghebretatios, Sabrina Schaly, Rahul Thareja, Karan Arora, Satya Prakash
The pharmacokinetic profile of siRNA therapies is highly restricted by several intracellular and extracellular barriers that interfere with the delivery of siRNA successfully to the target site. siRNA is rapidly cleared from the blood with a very short circulation half-life (a few minutes) as a result of many combined factors. Firstly, siRNA is highly retained by the reticulo-endothelial system (RES), endosomes, and lysosomes. Secondly, it is highly vulnerable to degradation by endoribonucleases and exoribonucleases in the plasma and tissues [8,9]. Additionally, siRNAs are mainly excreted by glomerular filtration due to their small size. Moreover, the cellular internalization of siRNA is limited by the electrostatic repulsion between its negatively charged phosphate backbone and the anionic lipid bilayers of cell membranes. Also, the size of siRNA (7–8 nm in length) is larger than the thickness of the cell membrane (5 nm) [10–14]. The above-mentioned barriers provide an explanation for the limited number of approved siRNA therapies currently on the market. It also reveals the urgent need to develop new strategies that can deliver siRNA efficiently to targeted organs with minimum off-target effects.
The molecular structure and biological functions of RNA methylation, with special emphasis on the roles of RNA methylation in autoimmune diseases
Published in Critical Reviews in Clinical Laboratory Sciences, 2022
Wanwan Zhou, Xiao Wang, Jun Chang, Chenglong Cheng, Chenggui Miao
RNA methylation is involved in almost all steps of RNA metabolism, including RNA capping, splicing, translation, nuclear export, and stability. The protein complex DXO/Dom3Z catalyzes the conversion of improperly capped mRNAs to 5′ mono-phosphate RNAs, resulting in their degradation by 5′-3′ exoribonucleases. This activity enables DXO/Dom3Z to independently degrade uncovered RNAs and RNAs with unmethylated capping. DXO/Dom3Z knockout in cells results in a significant increase in the number of improperly capped pre-mRNAs. This suggests that there is an mRNA capping quality control mechanism in mammals in which DXO/Dom3Z plays a central role [67,68]. Furthermore, m6A is enriched in exons of 5′ and 3′ splicing sites, which are the binding regions of serine/arginine-rich protein 2 regulated by mRNA splicing.
Wolbachia-Virus interactions and arbovirus control through population replacement in mosquitoes
Published in Pathogens and Global Health, 2023
Thomas H Ant, Maria Vittoria Mancini, Cameron J McNamara, Stephanie M Rainey, Steven P Sinkins
The RBP exoribonuclease 1 (×RN1) has also been implicated in Wolbachia-mediated antiviral activity [6]. Part of the RNA decay pathway, XRN1 actively degrades some flaviviral RNAs leading to the accumulation of sfRNAs, which in turn reduces XRN1 activity as degradation stalls; it remains bound to the subgenomic flavivirus RNA (sfRNA), effectively inhibiting the enzyme [6]. This leads to a favorable environment for viral RNA replication. When Wolbachia is present however, there is less viral replication and thus a reduced accumulation of XRN1-inhibiting sfRNAs and a more rapid degradation of viral RNAs by XRN1, likely enhancing the antiviral effects of Wolbachia.