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Scientific Programmes

Structural Biology Programme

Genome Integrity and Structural Biology Group

Group Leader:  Rafael Fernández
Overview

Safeguarding the information stored in the genome is essential to all forms of life. Two cellular processes are key to guarantee that this information is maintained free from errors: DNA replication and DNA repair. These processes involve the action of many different proteins and macromolecular complexes. Importantly, when they don’t work properly, these pathways are compromised and the information contained on the DNA may be damaged or lost. This can have important deleterious effects and impede the normal functioning of the cell, ultimately leading to the development of disease. It is widely known that deregulation and/or malfunction of the protein machinery that safeguards our genome are a hallmark of cancer, both as a source and a consequence of it. But it still remains unclear how this happens at the molecular level. "The devil is in the detail", and our mission is to understand what and when goes wrong with these molecular machines to the highest level of detail so we can act on it to correct it, and prevent it from happening.

The macromolecules and macromolecular complexes that perform these tasks are just like real life machines, with intricate mechanisms that allow them to perform their activities and be regulated by other factors. Our goal is to understand the mechanisms through which they carry out their function and by which they are regulated. In order to achieve this, we use high resolution structural techniques, mainly cryo-electron microscopy (cryo-EM), to resolve their structures with a level of detail that allow us to define the position of the atoms that make up these proteins, and in this way, understand how they work. We combine these findings with biochemical studies, and other biophysical techniques in an integrative approach to figure out how these machines work, what goes wrong when they are involved in disease, and how to stop them.

Beyond fundamental research, the high-resolution structural information that we obtain not only allows us to further our mechanistic understanding, but also provides the necessary structural detail to carry out efficient drug development for relevant targets in cancer.