Special Issue "Catalytic Nucleic Acids"

Guest Editor
Dr. Lun-Quan Sun
Department of Molecular and Medical Biology, University of Technology Sydney, Australia
E-Mail:
Interests: anti-viral and anti-cancer gene therapy;-development of nucleic acid-based drugs; functional genomics; assay development and drug screening; disease models and their biology

Dear Colleagues,

The past decades have seen the rapid evolution of gene-silencing strategies based on catalytic nucleic acids. Since the discovery of self-cleavage and ligation activity of the group I intron, the expansion of research interest in catalytic nucleic acids has provided a valuable nonprotein resource for manipulating biomolecules. RNA-cleaving RNA enzymes or “ribozymes” hold center stage because of their tremendous potential for mediating gene inactivation. Recently a new class of catalytic nucleic acid made entirely of DNA has emerged through in vitro selection. DNA enzymes or deoxyribozyme with extraordinary RNA cleavage activity has already demonstrated their capacity for gene suppression both in vitro and in vivo. These new molecules, although rivaling the activity and stability of synthetic ribozymes, are limited equally by inefficient delivery to the intracellular target RNA. The challenge of in vivo delivery is being addressed with the assessment of a variety of approaches in animal models with the aim of bringing these compounds closer to the clinic.

Dr. Lun-Quan Sun
Guest Editor

Submission

• ribozyme
• DNAzyme
• deoxyribozyme
• in vitro selection
• gene silencing
• chemical modifications
• catalytic nucleic acids
• oligonucleotide delivery

Feature Papers

Manuscript ID: Molecules-catanuc-20091104-Dass-au
Type of Paper: Review
Title: Dz13: c-Jun Downregulation and Tumour Cell Death
Author: Crispin R. Dass
Affiliation: Department of Orthopaedics, St. Vincent’s Hospital Melbourne, P.O. Box 2900, Fitzroy VIC 3065, Australia; E-Mail: cris.dass@yahoo.com
Abstract: DNAzymes (DNA enzymes, deoxyribozymes) are synthetic, single-stranded DNA-based catalysts engineered to bind to their complementary sequence in a target messenger RNA (mRNA) through Watson–Crick rules for base-pairing and cleave the mRNA at predetermined phosphodiester linkages. Dz13, a DNAzyme that cleaves c-Jun mRNA, has been found to have efficacious effects against tumours directly, activity against tumour-induced angiogenesis, inhibition of neointima formation after arterial injury, and control of inflammatory responses. Recent studies in endothelial cells demonstrate that the off-target effects of Dz13 may in fact be driving some of these potentially therapeutic effects, though no mechanisms have been clearly defined in tumour cells. Recent data shows that Dz13 is capable of inhibiting more types of tumours, and potently induces apoptosis in a panel of tumour cell lines. Hand-in-hand with in vivo testing, Dz13 has been formulated into a biocompatible nanoparticle, enabling its full potential to be realised. Its chemistry is partly responsible for its activity against tumour cells, but it is safe to use in vivo and surprisingly shows little harmful effects against normal cells. These findings provide hope that Dz13 may be useful clinically for treatment of a variety of cancers.
Keywords: Dz13; deoxyribozyme; DNAzyme; apoptosis; cancer; tumor

Manuscript ID: Molecules-catanuc-20091116-Cairns-au
Type of Paper: Review
Title: Gene Silencing with Catalytic DNA
Author: Murray Cairns
Affiliation: Neuroscience Institute of Schizophrenia and Allied Disorders, School of Biomedical Sciences, University of Newcastle, Newcastle, NSW Australia; E-Mail: Murray.Cairns@newcastle.edu.au
Abstract: Nucleic acids with their simple four-nucleotide chemistry and predictable affinity for complementary sequences are an appealing target for exogenous regulation of gene expression. Exploitation of hybridization as a means for achieving artificial gene suppression is mostly related to the advance of single stranded oligodeoxynucleotides (ODNs) and double stranded small interfering RNA (siRNA) based approaches, both of which have been successfully developed for laboratory and clinical applications. Other technologies with unique properties and attributes, may also find application in this area. This review looks at gene suppression mediated by RNA-cleaving catalytic DNA. These molecules interact with targets by hybridization and catalyze their cleavage/destruction without requiring any host-encoded proteins. The nuclease independent activity of catalytic DNA or DNAzymes may provide some opportunities that are currently beyond the scope of RNAi pathway-dependent siRNA and ribonuclease H-dependent ODNs.

Type of Paper: Review
Title: The Structural Diversity of Deoxyribozymes
Authors: Simon McManus and Yingfu Li
Affiliation: Department of Biochemistry and Biomedical Sciences, McMaster University, Canada; E-Mail: liying@mcmaster.ca (Y.L.)
Abstract: When not constrained to long double-helical arrangements as seen in chromosomes, DNA is capable of forming structural arrangements that enable specific sequences to perform functions such as binding and catalysis under specific conditions. Through a process known as in vitro selection, numerous catalytic DNAs, known as deoxyribozymes, have been isolated. Many of these molecules have the potential to act as therapeutic agents and diagnostic tools. As such, a better understanding of the structural arrangements present in these functional DNAs will aid further efforts in the development and optimization of these useful molecules. Structural characterization of several deoxyribozymes through mutagenesis, in vitro re-selection, chemical probing and circular dichroism has revealed many distinct and elaborate structural classes. Deoxyribozymes have been found to contain diverse conformations including helical junctions, pseudoknots, triplexes, and guanine quadruplexes. Some of these studies have further shown the repeated isolation of similar structural motifs in independent selection experiments, suggesting that particular motifs may be well suited for catalysis. To investigate the structural diversity possible in deoxyribozymes, a group of kinase deoxyribozymes have been extensively characterized. Such studies provided useful insight into the types of structures that are preferred to catalyze this reaction, while revealing some novel DNA structures.