The project aimed at understanding the molecular basis of function of ATRX, a protein that when mutated causes ATRX syndrome. Using structure-function approaches, our investigations addressed different aspects of ATRX function in cells.
ATRX syndrome is characterized by severe mental retardation, thalassemia, facial deformities and disability. ATRX is a serious genetic disorder, which results in a considerable increase in both acute and chronic morbidity, and mortality. Although ATRX is a rare disease, treatment is intensive and the lifetime cost of treating an ATRX patient is estimated to be ~£800,000. There is potential for commercialisation and exploitation of the scientific knowledge originated from this research as understanding how ATRX interacts with its target sequences may provide new druggable targets. Moreover, ATRX has also been implicated in many cancers, particularly in sarcomas, and the knowledge gained from our work will also improve the tools available to diagnose and treat cancers that display ATRX deregulation.
The overall aim of the project was to define at a molecular level how ATRX remodels chromatin.
Objective 1: To elucidate the structure of ATRX Snf2 domain by X-ray crystallography at various steps in ATP hydrolysis cycle
Objective 2: To investigate the structural preference of ATRX for various DNA substrates that are likely to be formed at interstitial repeat regions where ATRX is known to bind in vivo.
Objective 3: To investigate the interaction of ATRX with DAXX and Histone 3.3
Our main result from this project was the dissection of the ATRX - MeCP2 interaction in the context of the ATRX/RETT syndrome mutations. We were able to show direct interaction between ATRX and MeCP2. We have observed that this interaction is abrogated by most of the RETT-causing mutations in MeCP2. We are at present investigating if ATRX syndrome-causing mutations in ATRX also affect this interaction.
