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Research in Molecular Biology

Ongoing research projects in molecular biology focus on the molecular analysis of structure and function of biologically important proteins.
Current studies include:

Molecular analysis of inherited visual diseases:
The ROS ABC protein (ABCR) plays an important role in retinal rod cells. Genetic studies have linked mutations in the ABCR gene to a number of inherited human diseases including Stargardts macular degeneration and age related macular degeneration (ARMD).

Like other members of the ABC gene family, the ABCR protein is characterized by two nucleotide binding motifs and two transmembrane domains, each consisting of six membrane-spanning helices. Biochemical studies have suggested that this protein may function as a flipase, moving compounds from the lumenal to the cytosolic face of the disc membrane.

Our aim is to carry out a detailed molecular analysis of the ATP binding domains in the energy transduction process. In particular, the effect on ATP binding and hydrolysis, of mutations previously associated with inherited visual disease will investigated using recombinant proteins harboring mutations in these domains. Information gained from these studies will not only lead to an understanding of the mechanism of action of the ABCR protein, but will also give insight into the molecular basis of the diseases arising from mutations in this gene.

Hexameric DNA helicases and control of cell proliferation:
DNA helicases are enzymes that unwind the DNA double helix during various nuclear processes such as DNA replication, transcription and repair. Helicases are highly specific and the enzyme which functions in chromosomal DNA replication is distinct from that which functions in DNA repair or transcription. A hallmark of the majority of cancers is the rapid proliferation of neoplastic cells. Rapid cell division requires concomitant DNA replication in order for cell division to occur. Consequently, inhibitors against the DNA replication helicase would provide a novel form of chemotherapy that would specifically target rapidly proliferating cells. The replicative DNA helicases in eukaryotic systems are poorly understood at the present time. However, the DnaB protein, which has been shown unequivocally to function during DNA replication in E. coli serves as a prototypical model for the function of this class of enzymes. This protein provides us with a model system in which to study the structure and function of a replicative DNA helicase, so that inhibitors directed against its mechanism of action can be developed.

The benefits of this research for the treatment of cancer are: (1) the information gained can be used in the development of novel chemotheraputic drugs which inhibit cell proliferation, and (2) they will aid in the development of new classes of antibiotics useful in the treatment of drug resistant strains of bacteria. This is particularly important for cancer patients who often become immuno-compromised as a result of cancer chemotherapy.

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