Hammerhead ribozymes in therapeutic target discovery and validation

Tedeschi, Lorena; Lande, Caterina; Cecchettini, Antonella; Citti, Lorenzo

doi:10.1016/j.drudis.2009.05.003

Cited by 24 publications

(18 citation statements)

References 56 publications

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“…Although designed minimal HHRs successfully cleave target mRNA in vivo (Goodchild 2002;Citti and Rainaldi 2005;Tedeschi et al 2009), many studies have shown that ribozyme activity is highly restricted by not only target accessibility but also by the low physiological concentration of Mg 2+ (Castanotto et al 2002). Cleavage activity of the ribozymes in this study significantly decreased at a physiological Mg 2+ concentration of 0.1 mM (data not shown).…”

Section: Discussionmentioning

confidence: 74%

“…Ribozyme design for RNA-editing-specific cleavage based on HHR structure Because of their specificity for the NHH base triplet, transacting HHRs have been used as mutation-specific RNA cleavage tools (Goodchild 2002;Citti and Rainaldi 2005;Tedeschi et al 2009). However, HHR cleavage activity is significantly affected by not only the NHH preference, but also by base-pairing close to the catalytic core sequence (Werner and Uhlenbeck 1995).…”

Section: Resultsmentioning

confidence: 99%

“…The hammerhead ribozyme (HHR), which is the smallest catalytic RNA motif, can cleave the RNA phosphodiester bond at a specific site. Minimal trans-cleaving HHRs have been engineered by modifying natural HHRs (Uhlenbeck 1987;Haseloff and Gerlach 1988) and have been utilized for RNA-mediated gene regulation to inhibit target gene expression in vivo (Goodchild 2002;Citti and Rainaldi 2005;Tedeschi et al 2009). HHR consists of two sequence elements, including a conserved central catalytic core and two hybridizing arms for recognizing the target sequence.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

A strategy for developing a hammerhead ribozyme for selective RNA cleavage depending on substitutional RNA editing

Fukuda¹,

Kurihara²,

Tanaka³

et al. 2012

RNA

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Substitutional RNA editing plays a crucial role in the regulation of biological processes. Cleavage of target RNA that depends on the specific site of substitutional RNA editing is a useful tool for analyzing and regulating intracellular processes related to RNA editing. Hammerhead ribozymes have been utilized as small catalytic RNAs for cleaving target RNA at a specific site and may be used for RNA-editing-specific RNA cleavage. Here we reveal a design strategy for a hammerhead ribozyme that specifically recognizes adenosine to inosine (A-to-I) and cytosine to uracil (C-to-U) substitutional RNA-editing sites and cleaves target RNA. Because the hammerhead ribozyme cleaves one base upstream of the target-editing site, the base that pairs with the targetediting site was utilized for recognition. RNA-editing-specific ribozymes were designed such that the recognition base paired only with the edited base. These ribozymes showed A-to-I and C-to-U editing-specific cleavage activity against synthetic serotonin receptor 2C and apolipoprotein B mRNA fragments in vitro, respectively. Additionally, the ribozyme designed for recognizing A-to-I RNA editing at the Q/R site on filamin A (FLNA) showed editing-specific cleavage activity against physiologically edited FLNA mRNA extracted from cells. We demonstrated that our strategy is effective for cleaving target RNA in an editing-dependent manner. The data in this study provided an experimental basis for the RNA-editing-dependent degradation of specific target RNA in vivo.

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Section: Discussionmentioning

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

A strategy for developing a hammerhead ribozyme for selective RNA cleavage depending on substitutional RNA editing

Fukuda¹,

Kurihara²,

Tanaka³

et al. 2012

RNA

View full text Add to dashboard Cite

show abstract

“…The hammerhead, hairpin and hepatitis delta virus (HDV) ribozyme motifs can be characterized by their ability for self-cleavage of a particular phosphodiester bond. Hammerhead ribozymes have the ability to suppress gene expression through specific cleavage of RNA molecules Tedeschi et al, 2009). Langlois et al designed a hammerhead ribozyme with significant accessibility to a specific target site within the 3' UTR of the DMPK mRNA.…”

Section: Targeting the Mutant Dmpk Transcriptsmentioning

confidence: 99%

Myotonic Dystrophy Type 1: Focus on the RNA Pathology and Therapy

Mastroyiannopoulos¹,

Koutsoulidou²,

Phylactou³

2012

Muscular Dystrophy

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“…23 Since 1982, when the Nobel Prize committee recognized the discovery of RNA catalytic properties 24 as groundbreaking, 25 several "big" catalytic RNAs have been exploited for various biotechnological and medical applications. The catalytic RNAs that have made exciting headlines include group II introns, 26 RNase P, 27 the group I ribozyme, 28 and the Hammerhead catalytic module 29 (also known as the Hammerhead ribozyme-HHR). These applications represent some of the first developments that preceded small regulatory RNAs in the Synthetic Biology field.…”

Section: Introductionmentioning

confidence: 99%