Computational Selection and Experimental Validation of Allosteric Ribozymes That Sense a Specific Sequence of Human Telomerase Reverse Transcriptase mRNAs as Universal Anticancer Therapy Agents

Penchovsky, Robert; Kostova, Gergana

doi:10.1089/nat.2013.0446

Cited by 15 publications

(5 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Such aptazymes have been used as versatile tools in synthetic biology. These are useful as biological sensors [16][17][18][19], for bio-computing [20,21] and for potential therapeutic applications [22][23][24].…”

Section: Introductionmentioning

confidence: 99%

Highly motif- and organism-dependent effects of naturally occurring hammerhead ribozyme sequences on gene expression

2017

View full text Add to dashboard Cite

Recent bioinformatics studies have demonstrated a wide-spread occurrence of the hammerhead ribozyme (HHR) and similar small endonucleolytic RNA motifs in all domains of life. It is becoming increasingly evident that such ribozyme motifs participate in important genetic processes in diverse organisms. Although the HHR motif has been studied for more than three decades, only little is known about the consequences of ribozyme activity on gene expression. In the present study we analysed eight different naturally occurring HHR sequences in diverse genetic and organismal contexts. We investigated the influence of active ribozymes incorporated into mRNAs in mammalian, yeast and bacterial expression systems. The experiments show an unexpectedly high degree of organism-specific variability of ribozyme-mediated effects on gene expression. The presented findings demonstrate that ribozyme cleavage profoundly affect gene expression. However, the extent of this effect varies and depends strongly on the respective genetic context. The fast-cleaving type 3 HHRs [CChMVd(-) and sLTSV(-)] generally tended to cause the strongest effects on intracellular gene expression. The presented results are important in order to address potential functions of naturally occurring ribozymes in RNA processing and post-transcriptional regulation of gene expression. Additionally, our results are of interest for biotechnology and synthetic biology approaches that aim at the utilisation of self-cleaving ribozymes as widely applicable tools for controlling genetic processes.

show abstract

Section: Introductionmentioning

confidence: 99%

Highly motif- and organism-dependent effects of naturally occurring hammerhead ribozyme sequences on gene expression

2017

View full text Add to dashboard Cite

show abstract

“…Subsequently, Hao et al suggested that this RZ was very effective in inhibiting the expression of hTERT and strongly suppressing telomerase activity; this finally led to the induction of the rapid cell apoptosis of SW480 and SGC7901 cell lines by a telomere lengthening‐independent pathway. Recently, Penchovsky et al found a novel computational approach for selecting allosteric RZs that area sensitive to a specific sequence of hTERT mRNAs. In addition, several studies indicated that the trans‐splicing RZ might be a novel and potent anticancer agent as it can target a cancer‐specific transcript and replace it with new RNA.…”

Section: Ribozymesmentioning

confidence: 99%

Therapeutic strategies for targeting telomerase in cancer

Chen

Tang

Shi

et al. 2019

Medicinal Research Reviews

View full text Add to dashboard Cite

Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere‐based therapies such as nucleoside analogs, non‐nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere‐based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.

show abstract

“…In cultured cells transfected with the maxizyme only in leukemic cells presenting the BCR‐ABL fusion gene showed apoptosis. In addition, a HHR that detects a specific sequence of the human telomerase mRNA was developed using an in silico selection approach . In another example, an oligonucleotide‐dependent hairpin ribozyme developed by Famulok and coworkers contains a sensor domain that is complementary to the trp leader mRNA, which binds the l ‐tryptophan‐activated trp RNA‐binding attenuation protein (TRAP).…”

Section: Artificial Ligand‐dependent Ribozymesmentioning

confidence: 99%

Ligand‐dependent ribozymes

Felletti

Hartig

2016

WIREs RNA

View full text Add to dashboard Cite

The discovery of catalytic RNA (ribozymes) more than 30 years ago significantly widened the horizon of RNA-based functions in natural systems. Similarly to the activity of protein enzymes that are often modulated by the presence of an interaction partner, some examples of naturally occurring ribozymes are influenced by ligands that can either act as cofactors or allosteric modulators. Recent discoveries of new and widespread ribozyme motifs in many different genetic contexts point toward the existence of further ligand-dependent RNA catalysts. In addition to the presence of ligand-dependent ribozymes in nature, researchers have engineered ligand dependency into natural and artificial ribozymes. Because RNA functions can often be assembled in a truly modular way, many different systems have been obtained utilizing different ligand-sensing domains and ribozyme activities in diverse applications. We summarize the occurrence of ligand-dependent ribozymes in nature and the many examples realized by researchers that engineered ligand-dependent catalytic RNA motifs. We will also highlight methods for obtaining ligand dependency as well as discuss the many interesting applications of ligand-controlled catalytic RNAs. WIREs RNA 2017, 8:e1395. doi: 10.1002/wrna.1395 For further resources related to this article, please visit the WIREs website.

show abstract

Computational Selection and Experimental Validation of Allosteric Ribozymes That Sense a Specific Sequence of Human Telomerase Reverse Transcriptase mRNAs as Universal Anticancer Therapy Agents

Cited by 15 publications

References 35 publications

Highly motif- and organism-dependent effects of naturally occurring hammerhead ribozyme sequences on gene expression

Highly motif- and organism-dependent effects of naturally occurring hammerhead ribozyme sequences on gene expression

Therapeutic strategies for targeting telomerase in cancer

Ligand‐dependent ribozymes

Contact Info

Product

Resources

About