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Proposing Institution

Genzentrum LMU, AG Hopfner
Project Manager

Dr. Dirk Kostrewa
Feodor-Lynen-Straße 25
81377 München
We are interested in the structural biology of ‘macromolecular machines’, complex assemblies of proteins within the cell that typically convert chemical energy into mechanical work. The focus of our work is on a number of these complexes that play crucial roles in the response to cellular stress - such as DNA damage, infection by pathogens or changes in the environment – and thus protect the cell from the onset of disease.In order to gain a full understanding on an atomic level how such macromolecular machines are activated and function in response to stress, it necessary to determine their three-dimensional structures at near-atomic resolution in various conformational states. The study of such complexes by traditionally-used techniques (such as X-ray crystallography and nuclear magnetic resonance spectroscopy) is challenging because of the nature of the samples. Owing to recent hardware and software advances, cryo-EM is becoming the favoured technique to determine the structures of such complexes. A side effect of these advances is that the computational requirements have risen considerably, such that access to high-performance computing facilities is a necessity.Our work is focused on two aspects of genome maintenance in particular – the repair of DNA double-strand breaks and the remodeling of chromatin. Double-strand breaks are one of the most dangerous lesions, arising from errors during DNA replication as well as through exposure to ionizing radiation or genotoxic agents. If such breaks are left unrepaired or poorly repaired they can result in chromosome translations or an accumulation of mutations that drive the cell towards a cancerous state. Knowledge of how the repair factors function will provide insight into how they protect the cell against damage and will aid the design of therapeutics in the fight against the associated diseases. In a related project we are interested in understanding how macromolecular machines remodel chromatin in order to protect the DNA from damage, change the levels of gene expression and allow replication of the genome.

Impressum, Conny Wendler