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Structural Biology Programme

Macromolecular Complexes in DNA Damage Response Group

Group Leader:  Óscar Llorca
Overview

Avoiding cancer requires active DNA repair mechanisms. Also, tumour progression needs down-regulation of the cell response to DNA damage (known as DNA damage response or DDR). Large and dynamic macromolecular complexes perform many of the activities of the DDR. Large complexes survey the DNA looking for any sign of damage, detecting and repairing the lesions. Macromolecular complexes also send signals to the cell so that it responds adequately to the damage. We cannot fully understand these biological reactions without understanding the structure of the participating molecules and how they interact. Our aim is to study the structural architecture of these large complexes and understand how they function. This is of significant academic interest, but it also provides valuable structural information for targeted cancer therapy based on molecular mechanisms. We are interested in several DDR processes of relevance in cancer, including DNA repair, DNA damage response signalling, DNA replication, and RNA quality surveillance mechanisms.

Our main current research focus is improving our understanding of the regulation of the phosphatidylinositol-3-kinase-like family of kinases (PIKKs). PIKKs are large kinases including DNA-PKcs, ATM and ATR that participate in DNA repair and the DNA damage response, as well as mTOR controlling cell growth and SMG1, a protein involved in surveillance for some aberrant mRNAs as well as regulating gene expression by controlling mRNA degradation. These kinases are large in size and they work as part of even larger multi-subunit complexes. It was recently discovered that the assembly and maturation of these large PIKK complexes requires a dedicated HSP90 co-chaperone complex, the so-called R2TP complex. We are working to solve the structure of R2TP and to define the molecular mechanisms by which R2TP assembles the PIKKs as well as other complexes of relevance in cancer. Also we are exploring how the cell regulates PIKK function by controlling the maturation of these kinases.

We use cryo-Electron Microscopy (cryo-EM) as our main structural approach. Cryo-EM methods are revolutionising Biology, and we can now explore the structure of complexes at close-to-atomic resolution by observing individual molecules in the electron microscope. Cryo-EM is expanding the prospect of what we can do, since we can visualise complexes with great detail and using moderate amounts of sample. The methods are advancing rapidly to become of extraordinary value as help in drug discovery. This technology will be incorporated to CNIO.