The Oxford Science Lecture Series

Dr Elena Conti

Gene Expression Unit, European Molecular Biology Laboratory, Heidelberg, Germany

"Making sense of nonsense: structural studies of RNA degradation and disease"

Dorothy Hodgkin Memorial Lecture 2006

University Museum, Oxford, 9th March 2006

Dr Elena Conti is a group leader in the Gene Expression Unit at the European Molecular Biology Laboratory in Germany. Her work uses x-ray crystallography to study the structure and function of proteins involved in disease and thus extends from the pioneering work of Dorothy Hodgkin. This lecture was organised by the Oxford International Women's Festival with the support of Oxford AwiSE, Somerville College and The University Museum of Natural History.

The central dogma of biology tells us that the structure of DNA is translated into RNA which in turn provides the template for the formation of proteins. Although we can calculate the linear structure of a protein from the DNA sequence that produces it, this gives us limited information about the function of that protein. The crystal structure of a protein, on the other hand, gives a good crystallographer an immediate idea about its function. Comparison of the structure with that of proteins whose function is known can give valuable insights into how the protein works.

Dr Conti is interested in the molecular mechanisms that govern the transport of nuclear proteins and RNAs from their site of synthesis to their site of function. Many diseases are caused by mutations in RNA. Transport of RNA from the nucleus to the cytosol of cells is limited by several mechanisms that make sure that only correctly transcribed and processed RNAs are exported and translated. One of the errors that has been found to occur in the transcription of DNA into RNA results in “nonsense mutations” which prematurely halt the process that produces the protein. A quality control process exists that detects the RNA containing these “nonsense mutations” and degrades it before it gives rise to truncated and potentially harmful protein products. However in some diseases, such as certain forms of cystic fibrosis, it is the destruction of the RNA containing a “nonsense mutation” that leads to the disease since the proteins that are no longer formed are critical to the function of the body. The work of Dr Conti’s laboratory involves studying the crystal structures of enzymes involved in this degradation mechanism. They have established that the molecules contain a central core through which portions of RNA are threaded and then degraded. If these sites of action are blocked then the function of the enzyme is inhibited. The mutated RNA is no longer degraded and a truncated protein is formed. It is hoped that the presence of this truncated protein may be sufficient to prevent the progression of the disease.

Dr Carolyn Carr, Cardiac Metabolism Research Group, University of Oxford.