Investigation of the translational regulation of terminal oligo pyrimidine (TOP) containing mRNAs

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Our bodies' cells are built from a diverse set of building blocks called proteins. All proteins can be made by translating specific pieces of the DNA genetic code. An intermediate material called mRNA is used between DNA and proteins; it presents the parts of the genetic code for proteins needed at a particular time and place to the machinery that translates it into proteins. The 'molecular factory' that translates mRNA into proteins is called the ribosome, made itself of a mixture of about 80 RNAs and proteins. Without ribosomes, no proteins could ever be made. When our cells grow and divide, the number of each of the component parts of ribosomes also has to double so that enough proteins can continue to be made. Incorrect proportions of component parts of the ribosome can cause cells not to grow enough, or to grow too much, and so imbalances can lead to diseases such as cancer. The many proteins whose job is to work as part the ribosome have a unique 'tag' (called a TOP or terminal oligopyrimidine tract) in the mRNA that encodes them. All mRNAs with this tag have their translation closely co-ordinated by existing ribosomes so that their proteins are made at the same time and rate. While we know about the existence of the tag, we do not fully understand how it is recognized and used to control new ribosome manufacture. Our lab has done initial experiments which reveal a unique suite of proteins that bind to the tag. In this application we propose to study exactly how these proteins interact with the tag, and with each other, to co-ordinate ribosome manufacture so accurately. Our results could help us to understand how cancers develop when this goes wrong, and, in the longer term, could provide new ways to tackle this disease.