Towards a mechanistic understanding of RNA processing machines

Sleeping sickness, Chagas disease and leishmaniasis are common in tropical and subtropical areas. These diseases are deadly but they are largely ignored by pharmaceutical companies. They are caused by a family of single-celled parasites called kinetoplastids. In all living organisms, genetic instructions for making proteins require messenger RNAs (mRNAs), which are short-lived copies of DNA. Unlike their human hosts, kinetoplastids produce some of their mRNAs in an incomplete, encrypted form. They need to be edited or re-written in a specific way to allow production of the proteins that are essential to the parasite’s survival. A remarkable and unique molecular ‘machine’ containing 14–15 different protein molecules is responsible for the RNA editing process. This is not found in humans and is essential for parasite survival, so it is an attractive target for drug development. However, we have limited information about this machinery works.

We will capture snapshots of individual parts of the machine during the editing process and examine their structures to understand how they work.

Our findings could highlight potential new directions for drug development for these diseases.