Enzyme silencer for miRNA
doi:10.1038/nindia.2009.73 Published online 27 February 2009
In an easy-to-design technique that could have wide-ranging applications in disease diagnostics and therapeutics, researchers have managed to cripple the activity of a new class of small RNAs — tiny workhorses responsible for gene expression and protein synthesis in our body1. This will further our knowledge of the functions of this class of RNAs — called miRNAs — in disease progression and ultimately in finding new therapeutic targets for treatment.
MicroRNAs are tiny molecules containing 22 bases. These RNAs don't produce proteins, but they bind to mRNAs or messenger RNAs, which translate instructions from genes to create proteins. These miRNAs suppress expression of genes and protein production. Faulty miRNAs and their targets may lead to various diseases, such as cancers, cardiovascular disease, schizophrenia, and renal function disorders.
But being extremely small, miRNAs are difficult to detect and study. To overcome this, a team of researchers from New Delhi's Institute for Genomics and Integrative Biology (IGIB) used short nucleic acid polymer enzymes known as DNA antagomirzymes (DZs) or DNAzymes to cleave and silence miRNA and study its role. They also used locked nucleic acid (LNA) to modify DNAzymes giving rise to two other polymer enzymes - LZ2 and LZ4.
The team worked on a cluster of two human miRNAs — hsa-miR-372 and hsa-miR-373 — which are known to be specifically malfunctioning and directly involved in the disease progression of reproductive cell tumors. They found that in a lab dish, the polymer enzymes LZ2 and LZ4 cleaved greater than 75 per cent of the human miRNAs compared to about 60 per cent by DZ. Through a series of similar tests in cultured human embryonic kidney cells, they confirmed that LZ2 and LZ4 worked better in silencing human RNAs than DZ.
Studies have shown that miRNAs exhibit a protective effect against cancer. But in some cancers, the levels of miRNA are elevated. "In our study, we have shown a reduction in the levels of miR-372/373, which shoots up in tumours of reproductive cells," says lead researcher Souvik Maiti. "This is the first approach to cleave and silence the activity of specific miRNAs using such enzymes," Maiti says. The ease with which the enzymes can be designed and used makes them ideal candidates for diagnostics and therapeutic purposes, he adds.
There are a number of miRNAs encoded by viruses (especially cancer-causing viruses of the Herpes family), which produce miRNAs to target human hosts. These synthetic polymer enzymes will be a very attractive therapeutic options to downregulate such RNAs, Maiti says.
- Jadhav, M. V. et al. Antagomirzymes: Oligonucleotide Enzymes That Specifically Silence MicroRNA Function. Angew. Chem. Int. Ed. doi: 10.1002/anie.200805521 (2009)