Nature Structural Biology pp 120 - 125

Cells splice bits of a gene together to make a mature RNA template for protein synthesis. This process generates useful protein diversity, but skipping over parts of the gene by mistake when assembling the template can lead to disease. A paper in the February issue of Nature Structural Biology shows how synthetic molecules prevent such skipping and restore the healthy 'splicing' of defective genes.

Single nucleotide mutations often lead to aberrant RNA splicing. Some of these mutations affect the recruitment of cellular components that promote splicing, thereby creating an RNA template that lacks an important segment of a gene. To correct this type of splicing defect, Cartegni and Krainer (Cold Spring Harbor Laboratory, USA) developed synthetic molecules that can recruit the splicing machinery to the faulty RNA regions. These compounds contain two components: one that specifically binds the defective RNA and the other that mimics the function of SR proteins, which recruit the machinery. In two test cases, the hybrid compounds successfully rescue the skipping splicing defect in a breast cancer gene and in a muscular atrophy gene. These compounds may thus represent a potential therapeutic approach to correct splicing defects in human disease.

Nature Structural Biology pp 91 - 92

RNA interference (RNAi) is one of the hottest topics in science these days. The ability of small RNA molecules to inhibit the expression of specific genes has made RNAi an extremely useful tool in modern biology. A paper in the February issue of Nature Structural Biology reports the creation of transgenic mice, in which inherited RNAi lowers the expression of a target gene. The result extends the power of RNAi to genetic studies in live animals.

RNAi generates genome diversity, is a host-defense mechanism and controls gene expression through regulatory feedback mechanisms. It is also a tremendously promising tool in stem cell research and tissue engineering. To make RNAi a viable tool to study the functions of genes in mice, Rosenquist, Hannon and collaborators (State University of New York at Stony Brook and Cold Spring Harbor Laboratory, USA) generated embryonic stem cells containing an RNAi signal targeted to a specific gene. Chimeric animals produced using these cells had offspring that inherited the RNAi signal and showed a lowered expression of the target gene. The creation of germline transgenic mice with an engineered and effective RNAi pathway opens the door to the manipulation of gene activity in living animals.