JAY D. GRALLA
Professor of Biochemistry and Molecular Biology; BS, Chemistry,
Clarkson College; PhD, Biophysics, Yale University; Jane Coffin Childs
Fellow in Molecular Biology, Harvard University; EMBO Fellow in
Biochemical Oncology, Pasteur Institute, France.
The ability of a cell to function normally and carry out its
specialized functions depends critically on the proper regulation and
expression of its genes. This regulation has its roots in the diversity
and specificity of interactions between biological macromolecules. At the
level of control of transcription this means primarily the interactions
between promoter DNA sequences and proteins and the interactions of
proteins with each other. We study how these interactions occur and what
they do to control the process of gene transcription. We also study what
is wrong with these interactions when mutations cause defects in
transcription and how certain anti-cancer drugs might influence the
expression of the mutant and normal genes.
The approach used relies on comparing transcriptional control in
reconstructed systems with that occurring inside cells. We have
developed chemistry-based procedures for probing the interactions of
proteins with DNA inside cells. These are applied to both mammalian
and bacterial cells under conditions where the activity of genes may
be controlled by biological means. The results lead to models for what
types of nucleoprotein complexes assemble when genes are active and how this changes when they are inactivated by mutation or by biological repression.
These models are tested by isolating the regulatory macromolecules from
cells and reconstructing the system in vitro. In some cases the
isolated proteins are then mutated to learn the roles of specific protein domains in transcriptional regulation. The picture that is emerging
promises to contribute significantly to our understanding of what goes
wrong when cells specify inappropriate patterns of gene transcription
and are converted to the transformed state.
Biochemistry: DNA biochemistry; protein-DNA and protein-protein
interactions; control of transcription; mammalian promoters; anti-tumor
drugs; bacterial enhancers.