Critical Reviews in Oral Biology & Medicine, Vol 12, 469-478, Copyright © 2001 by International & American Associations for Dental Research
Synthetic hammerhead ribozymes as tools in gene expression
S. P. Lyngstadaas
Oral Research Laboratory, Faculty of Dentistry, University of Oslo, Blindern, Norway. spl@odont.uio.no
The assessment of genetic controls for sequential developmental processes
such as tooth formation and biomineralization is often difficult in
transgenic "knockout" models, where phenotypes reflect only the permanent
eradication of a gene, and reveal little about the dynamic range of
expression for the gene(s) involved. One promising strategy to overcome
this problem is through the use of ribozymes, a class of metalloenzymes
made entirely of ribonucleic acid (RNA), that are capable of cleaving other
RNA molecules in a catalytic fashion. Their activity can be targeted
against specific mRNAs by selection of unique sequences flanking a
conserved catalytic motif. In synthetic ribozymes, specificity, stability,
and cell permeability can be dramatically improved by the incorporation of
chemically modified ribonucleotides. This review focuses on the design and
application of hammerhead ribozymes, the best-known and most widely used
class of RNA-based enzymes. So far, except for a few conserved structures
at the catalytic core, no one particular model or superior ribozyme design
has been identified. It may well be that each cell, tissue, and organism
has different requirements for the uptake, activity, and stability of
hammerhead ribozymes. However, designed ribozymes can be highly effective
agents for timed and localized elimination of gene products. As the 3D
structures of active hammerhead molecules are revealed, more effective
ribozymes will be developed. Today, developments in ribozyme-mediated
sequence-specific blocking of gene expression hold great promise for active
RNA enzymes as tools in biomolecular research and for eliminating unwanted
gene expression in human diseases.
