Newswise LA JOLLA, CA May 9, 2013 A team led by scientists at The Scripps Research Institute (TSRI) has found how to boost or inhibit a gene-silencing mechanism that normally serves as a major controller of cells activities. The discovery could lead to a powerful new class of drugs against viral infections, cancers and other diseases.

Learning to control natural gene silencing processes will allow an entirely new approach to treating human disease, said Ian J. MacRae, assistant professor in TSRIs Department of Integrative Structural and Computational Biology and principal investigator for the study, which appears as the cover story in the May 9, 2013 issue of the journal Molecular Cell.

A Scientific Mystery and Technical Conundrum

The gene-silencer in question is Argonaute 2, a molecular machine in cells that can grab and destroy the RNA transcripts of specific genes, preventing them from being translated into proteins. Argonaute 2 and other Argonaute proteins regulate the influence of about a third of the genes found in humans and other mammalsand thus are among the most important modulators of our cells day-to-day activities. Argonautes gene-silencing functions also help cells cope with rogue genetic activity from invading viruses or cancer-promoting DNA mutations.

Yet Argonautes workings are complex and not yet entirely understood. For example, before it starts a search-and-destroy mission against a specific type of target RNA, an Argonaute 2 protein takes on board a target-recognition device: a short length of guide RNA, also known as a microRNA (miRNA). The miRNAs sequence is mostly complementary to the target RNAsa sort of chemical mirror-imageso that it can stick tightly to it.

But how do an Argonaute protein and its miRNA guide, having formed their partnership, manage to part company? It has been a scientific mystery and technical conundrum for researchers, who have found it hard to separate Argonaute proteins from miRNAs in the lab dish.

That problem led us to look for a way to get Argonautes to unload these miRNAs, said Nabanita De, a postdoctoral fellow in MacRaes laboratory who was first author of the new study.

Matches and Mismatches

In an initial set of experiments, the team demonstrated that when an miRNA hooks up with an Argonaute 2, the pair do remain locked together and functioning for an exceptionally long time: days to weeks, whereas solo miRNA normally is degraded within minutes.

Yet prior studies by other laboratories have hinted at the existence of mechanisms that can hasten the separation of miRNAs from Argonautes. Some viruses, for example, produce decoy target RNAs that virtually nullify the activity of the corresponding miRNAs, seemingly by destabilizing the miRNA-Argonaute pairing. A key feature of these decoy target RNAs is that they make an almost perfect complementary match to the miRNAsespecially at one end of the miRNAs, known as the three-prime or 3 end. In this respect, they match the miRNAs much better than the natural gene transcripts that the miRNAs evolved to target.

Link:
Scientists Find Key to Gene-Silencing Activity

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