Structure and function of chromatin remodelling ATPase's and their dysfunction in in human disease.

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The genomes of eukaryotes are associated with histone proteins to form a DNA protein complex called chromatin. The regulation of chromatin structure provides one means by which eukaryotic organisms regulated access to DNA. One means by which this is achieved involves the action of an extended family molecular motor proteins, known as chromatin remodelling ATPases. Recent advances to electron microscopy provide an opportunity to gain major new insights into how these motor proteins interact with chromatin. In this proposal we will apply advanced electron microscopy and image processing together with other complementary techniques to study how the shape of these motor proteins changes as they act to reconfigure chromatin. This will provide new insight into the process by which access to genes is regulated. It has recently become apparent that the genes that encode these motor proteins are often altered in cancer cells. We have noticed that these alterations repeatedly occur at a similar position on several different subtypes of motor proteins. Related alterations are also detected in some congenital diseases. As a result, we will systematically characterise how these alterations affect the way the motors work and determine which stage in the motors activity is blocked. We will also generate cell lines that will enable us to study the difference in between the loss of genes that encode motor proteins and the repeated alterations that are observed in cancers. We will find out whether cells are able to function normally when an altered copy of the motor gene is removed. If this is the case, blocking the altered motor and letting the cells carry on using the normal copy of the motor gene they typically retain may provide a way of treating patients. The proposal will generate a platform of knowledge from which new ways to target the defective motors can be devised.