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"We aim to shed light onto the fundamental DNA repair mechanism that once mutated results in Cockayne syndrome. Despite its biological importance, we currently have almost no mechanistic understanding of this process. "











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Electron density map used in structure determination.




"The ERC grant allows me to pursue an interdisciplinary approach and to bring structural biology to an area where currently no structural insights are available."

January 12, 2011

Kick-off of Nicolas Thomä's ERC grant study on Cockayne Syndrome

Nicolas Thomä, group leader at the Friedrich Miescher Institute for Biomedical Research, has received the European Research Council (ERC) Starting Independent Researcher Grant to study the molecular basis of Cockayne Syndrome. Cockayne Syndrome is a rare disease affecting children, characterized by accelerated aging. The disease is due to defective DNA repair within actively transcribed genes. Currently, there is no therapy for the disease and a molecular understanding of the fundamental biological processes gone awry in the disease is much needed.

Q: Nicolas, you have received your ERC grant for the structural and biochemical characterization of the Cockayne syndrome proteins and their role in DNA repair. Why is it so important to study this protein complex?

Nicolas Thomä: The integrity and the stability of the genome are paramount for the healthy development of a cell. They ultimately are also crucial for 'normal' human development. Mutations of proteins that safeguard the genome frequently result in cancer and often also trigger accelerated aging in patients.

We are interested in a specific repair process called transcription coupled repair. It is a fundamental process for which we know some of the protein players such as the Cockayne syndrome proteins (CSA and CSB), but we do not know what these proteins actually do and how they help find and repair DNA damages in actively transcribed genes. We will use structural biology to determine the three dimensional structure of these protein complexes and then use this structural insight to test and infer their biological function.

Q: The process you are studying has gone awry in a disease called Cockayne Syndrome. What are you expecting from this link?

NT: Cockayne Syndrome is a very debilitating congenital disease affecting children. These children carry a defect in their DNA repair machinery. While they are healthy at birth, children affected with Cockayne syndrome typically show signs of delayed development early in their childhood and subsequently develop many of the ailments typically associated with aging. The disease is relatively rare and is therefore often misdiagnosed sending patients and families onto an odyssey in search for the right diagnosis. Most of the children unfortunately die before they reach adulthood. Currently, there is no treatment for this rare disease.

Our work aims to shed light onto the fundamental DNA repair mechanism that once mutated results in Cockayne syndrome. Despite its biological importance, we currently have almost no mechanistic understanding of this process. Having recently met Cockayne syndrome children has additionally motivated me to participate with my lab in the search of the molecular cause of the disease. Understanding the mechanism will hopefully open new avenues in the search for a cure. Recent studies on a number of developmental and neurological aliments have suggested that, given the right treatment, these diseases are surprisingly reversible also in the later stages.

Q: You have been a group leader at the FMI since September 2006. What does this very competitive award mean to you??

NT: The ERC grant is very important. We can only solve this riddle with an interdisciplinary approach. Structure needs to complement function and vice versa. In my lab, over the last couple of years, we have developed an expertise for the structural and biochemical analysis of these huge macromolecular protein machines. The ERC grant allows me to pursue an interdisciplinary approach and to bring structural biology to an area where currently no structural insights are available. This will help to provide a novel angle into understanding the processes gone wrong in Cockayne syndrome. ää

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