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Structural Biology Programme

Genome Integrity and Structural Biology Group

Group Leader:  Rafael Fernández
Research highlights
Mismatch repair

DNA mismatch repair (MMR) is critical for genome stability. The DNA mismatch repair machinery loads onto newly synthesised DNA and searches for mismatches. The recognition of an error in DNA by the MutS protein leads to an ATP-dependent conformational change that transfers MutS into a sliding clamp state. Only this MutS state is able to activate the MutL ATPase that in turn promotes the cleavage of the DNA for repair. These protein complexes are extremely dynamic and flexible and many steps of the cycle have remained elusive to structural analysis. Using cryo-EM we capture multiple functional steps and we can now study the conformational changes that these proteins undergo in order to recognise the mismatch and license downstream events that lead to repair. These studies started during my postdoctoral research and will be continued at the CNIO in collaboration with Titia Sixma (Netherlands Cancer Research Institute) and Meindert Lamers (Leiden University).

DNA replication and repair—focus on mitochondria

Eukaryotic cells have two genomes: nuclear and mitochondrial. However, how the integrity of the mitochondrial genome is maintained through the equilibrium between DNA replication, repair and degradation, and organelle dynamics still remains unclear. We are interested in understanding these pathways because of their implications on ageing and disease, and in particular their relationship to cancer.

Cryo-electron microscopy (cryo-EM)

Important recent technological developments in microscopes, detectors and image processing tools have significantly improved the resolution of cryo-EM, enabling the structural analysis of many elusive macromolecules to an unprecedented level of detail. We are upgrading our cryo-EM facility and will have stateof-the-art equipment. Combined with many other approaches already established at CNIO, we use cryo-EM to study diverse macromolecular complexes involved in cancer.