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Structural studies of AT-rich DNA complexed with Minor Groove Binding Drugs, peptides and HMG proteins.

Type of activity
Competitive project
Funding entity
ALBA - Consorcio para la Construcción, Equipamento y Explotación del Laboratorio de Luz de Sincrotrón
Start date
End date
Abstract: In most genomes there is a large quantity of DNA which does not code for proteins. Its function is unknown. It may play a role in the structural stabilization of the cell nucleus, but it is not
clear what mechanisms/structures might be involved. In any case it is clear that non coding DNA is AT rich, often in the form of microsatellites with a repetitive sequence. In order to clarify the role
played by this type of DNA, we are studying the structural versatility of DNA with 100% AT. In the last few years we have discovered that it may form Hoogsteen duplexes, coiled coils, macroscopic helices,etc. More recently we have found that some drugs may act as cross-linking agents for DNA.
In view of the latter results we plan to explore the interaction of related drugs with 100% AT sequences. For these studies we must use the methods of X-ray crystallography. We will study minor groove binding drugs, which have been used as anti-protozoal agents in the fight against Malaria, Trypanosomiasis, Leishmaniosis, tuberculosis associated with AIDS, etc. Furthermore we will study the interaction of DNA with High Mobility Group proteins (HMG) and related peptides. The HMGA and HMGB proteins are found in all cells and interact with AT rich regions of DNA. Although the biological role of these proteins is known in many cases, the mode of interaction with DNA is not clear. We will also study a particular HMGB protein which is known to interact specifically with stretches of alternating AT-rich DNA. These studies will be complemented by the bioinformatics analysis of the distribution of 100% AT microsatellites in several genomes, in an attempt to understand their biological function.