Professor of Biological Chemistry
Director, Program in Biomedical Sciences
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My laboratory investigates several
aspects of eukaryotic gene expression, using yeast and
human model systems. A combination of biochemistry, molecular
genetics, and high resolution microscopy is used to study
the forces that both activate and silence nuclear transcription
units. We recently found that tRNA genes antagonize transcription
of other nearby promoters, and that this phenomenon is
related to the three dimensional organization of the activated
transcription units. This phenomenon is under study as
a potentially widespread negative regulatory mechanism.
In addition to transcription mechanisms, the lab studies
structures and functions of RNA enzymes, especially the
ubiquitous endoribonuclease RNase P. The highly ordered
tertiary structures of the RNA enzymes recognize and cleave
pre-tRNA and other substrates through shape recognition,
and the nuclear form of RNase P has developed an elaborate
subunit structure to allow discrimination of its role
in the complex nuclear RNA processing pathways. We are
studying how this complex holoenzyme structure recognizes
both substrates and elements of the nuclear architecture.
In related projects, we are exploring
the ability of nucleic acid chains to recognize a variety
of molecular targets, and to apply this knowledge to
practical problems. It has become possible to select
RNA (or modified RNA) molecules that bind tightly to
nearly any molecular surface, starting from a "library" of
more than a quadrillion sequences. This allows the production
of affinity tags, diagnostics, and potentially potent
inhibitors to a wide variety of targets that are not
necessarily amenable to antibody production. |