Related Experiment Video
Updated: Jan 2, 2026
Dual CRISPR-Interference Strategy for Targeting Synthetic Lethal Interactions Between Non-Coding RNAs in Cancer Cells
Published on: May 30, 2025
Cytotoxic ribonucleases and RNA interference (RNAi)
Barbara Ardelt1, Wojciech Ardelt, Zbigniew Darzynkiewicz
1Brander Cancer Research Institute, New York Medical College, 19 Bradhurst Avenue, Hawthorne, NY 10532, USA.
Abstract:
Several cytotoxic ribonucleases (CRs), homologs of the pancreatic RNase A, have been isolated from amphibian oocytes or embryos. Of them, onconase (Onc), the CR that shows antitumor properties and is in phase III clinical trials, was the most extensively researched. Degradation of tRNA by Onc internalized into cells that leads to inhibition of protein synthesis is considered the mechanism of its cytotoxicity. Several findings, however, cannot be explained by nonspecific decline in protein synthesis alone and suggest additional or alternative mechanism(s). We postulate therefore that miRNAs and/or RNA interference (RNAi) may also be targets of CRs. The following arguments support this postulate: (A) miRNAs and siRNAs appear to be unprotected by proteins and therefore, as tRNA, accessible and degradable by CRs; (B) Onc has preferred cleavage sites on tRNAs: their cleavage may generate segments of dsRNA that interfere with translation. Analogous to Dicer, thus, small RNAs with interfering properties may be generated by CRs within the cell; (C) CRs are abundant in oocytes and during embryonic development; their role there is unknown. Since cells undergo perpetual differentiation during embryogenesis it is likely that the function of CRs is to provide additional level of regulation of gene expression via the mechanisms listed in (A) and/or (B).
Insights
Cytotoxic ribonucleases (CRs) may target microRNAs (miRNAs) and RNA interference (RNAi) pathways, offering a novel mechanism beyond protein synthesis inhibition for their antitumor and developmental roles.
Area of Science:
- Biochemistry
- Molecular Biology
- Cell Biology
Background:
- Cytotoxic ribonucleases (CRs), homologs of pancreatic RNase A, are found in amphibian oocytes/embryos.
- Onconase (Onc), a CR with antitumor properties, is extensively studied for its tRNA degradation and protein synthesis inhibition mechanism.
Purpose of the Study:
- To investigate potential alternative mechanisms for CR cytotoxicity, specifically targeting microRNAs (miRNAs) and RNA interference (RNAi).
- To explore the role of CRs in gene expression regulation during embryonic development.
Main Methods:
- Literature review and analysis of existing findings on CRs, onconase, tRNA, miRNAs, and RNAi.
- Postulation of new hypotheses based on structural and functional properties of CRs and small RNAs.
Main Results:
- miRNAs and siRNAs are potentially unprotected and thus accessible to CRs.
- CRs may generate dsRNA fragments from tRNA cleavage, interfering with translation, similar to Dicer.
- CR abundance in oocytes suggests a role in regulating gene expression during embryogenesis.
Conclusions:
- CRs may exert cytotoxicity through mechanisms involving miRNA and RNAi pathways, in addition to tRNA degradation.
- CRs likely play a regulatory role in gene expression during embryonic development by targeting small RNA pathways.
