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Projects. Life and Earth Sciences

The development of molecular scalpels for the repair of genes involved in single gene diseases

Lead Researcher:
Guillermo Montoya Blanco

Research Centre:
Centro Nacional de Investigaciones Oncológicas. Madrid.

Synopsis: 

Guillermo Montoya BlancoThe engineering of protein-DNA interactions may give rise to new "tools" to modify the genome. Meganucleases and TALENs are powerful tools for the manipulation of the genome, creating in the double strands of DNA breakages that can be sealed by means of homologous recombination. These enzymes may cause breakages in the DNA chain of eukaryotic genomes with a high degree of specificity. To be able to redesign these enzymes for this purpose, the basis for recognition of the interaction between the protein and the sequence of nucleic acid must be teased out to generate tailored enzymes targeted at sites of interest within the DNA. The engineering of proteins in domains such as meganucleases, "zinc fingers" or TALEs, has been proved to have potential for these methods, to create new specific and targeted instruments for the inactivation or repair of certain genes. The personalization of these enzymes with a high specificity to recognise specific sequences of DNA is the key tool in a new targeted cell therapy that eliminates alterations and promotes cell repair. When this action is carried out in genes involved in single gene diseases, it would be possible to restore the original function of the defective genes in question. During this year, it has been shown that the 4 pairs of central bases in the DNA sequence of the 22-nucleotide substrate of the aI-CreI endonuclease (which do not show any specific protein-DNA interactions) do not lack information for the recognition of the DNA sequence. The data suggest that this substrate region plays an important role by the indirect reading of the target, opening up the possibility of a totally rational search for new sequences, thereby improving the development of enzymes redesigned for therapeutic and biotech applications. Additionally, the crystallographic structure has been resolved for a new protein domain of DNA interaction, potentially usable as the mould to generate new interactions with certain sequences.


Scientific production
2 articles published in Journals

Researcher's web address:

http://www.cnio.es/es/grupos/plantillas/presentacion.asp?grupo=50004291  



Guillermo Montoya Blanco

Guillermo Montoya was born in Madrid in 1967. He graduated in Biochemistry from the University of the Basque Country in 1990, and gained his doctorate in Chemistry from the University of Zaragoza in 1993. He was awarded grants by the European Molecular Biology Organisation (EMBO) and the Federation of European Biochemical Societies (FEBS) to undertake a postdoctoral stay, and he went to the Max Planck Biophysics Institute in Frankfurt am Main (Germany), where he worked on the crystallisation of membrane proteins in the group of H. Michel. Subsequently and thanks to an EMBO long-term grant and another Marie Curie grant (EU), he travelled to the European Molecular Biology Laboratory (EMBL) in Heidelberg (Germany), where he remained for 9 years performing pioneering studies of the structure of the signal recognition particle (SRP), a complex ribonucleoprotein essential in the biogenesis of membrane proteins. In 1998 he was named Researcher of the Superior Science Research Council (CSIC) and he was awarded a grant from the Peter und Traudl Engelhorn Foundation. From 2003 to 2008, he was Honorary Professor of Biochemistry in the Autonomous University, Madrid, and member of the working group assigned to the design of the light crystallography in the Spanish synchrotron (ALBA). By using protein engineering, the group of Dr. Montoya has redesigned the specificity of proteins recognising DNA. These redesigned enzymes may be used to stimulate homologous recombination by double chain breakage, inducing the repair of defective genes at very low levels of toxicity. The use of these redesigned proteins opens up new possibilities for gene therapy in patients with single gene diseases. In 2009 he was awarded the National Prizes of the Mutua Madrileña Foundation and the Caja Rural de Granada Foundation, Ministry of Health.


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