The
Canadian
Cancer Society estimates that there will be 153,100 new cases of cancer
and 70,400 deaths from cancer in
Scientists have found chromosome gain or loss,
or aneuploidy, in nearly all major
human tumour types. A major interest in the Baetz Lab is to discern the
genetic and molecular basis for chromosomal instability. In particular
we are interested in how DNA binding proteins and enzymes that regulate
chromatin structure - the combination
of DNA and core histone proteins - impact chromosome segregation and cell
cycle progression.
Why
is Baetz using the yeast
we commonly use for brewing beer to study cancer? Because the basic cellular
functions of yeast are nearly identical to those of humans. If we understand
the function of a protein in yeast, we'll be a lot closer to understanding
its function in mammalian cells.
In addition, yeast has been the model organism
for the development of functional genomic
and proteomic techniques that allow
for the assessment of all protein function within a cell. Thus, yeast is
recognized as a powerful substitute model organism for the study of mammalian
disease biology.
The
Baetz Lab's
current research projects combine both powerful high-throughput yeast chemical
and functional genomic screens with proteomic approaches in order to assess
which of yeast's 6,000 proteins play a role in maintaining chromosome balance
in the cell or cell cycle progression. Once the proteins are identified
traditional methods drawn from biochemistry and molecular biology are used
to reveal the molecular mechanisms used by these proteins to prevent chromosome
loss.
Chromatin and Chromosome Stability
Our
studies on Chromatin and Chromosome Stability are proceeding on multiple
fronts.
First,
we are continuing our characterization of the histone
acetyltransferase (HAT) NuA4 that we identified as a major regulator
of chromosome stability. NuA4 is a multisubunit protein complex and is
the only essential HAT in yeast. NuA4 mutants deficient in acetyltransferase
activity have huge increase in chromosome loss. Through integrated functional
genomic and proteomic approaches we are aiming to reveal the molecular mechanisms
used by NuA4 to maintain chromosome stability. In addition, the NuA4 interactome
network map we are generating will allow us to systematically determine
the cellular functions of NuA4.
Secondly,
through genome-wide screens we have recently shown that the iron responsive
transcription factor Aft1 has an important role in maintaining chromosome
stability. We are presently utilizing a variety of genome-wide synthetic
genetic interaction screens to examining the roles of Aft1 in cell cycle
progression.
Thirdly,
we are utilizing a variety of genomic and proteomic approaches in budding
yeast to identify novel regulators of chromatin structure whose function
contributes to genome stability. In particular we are interesting in determining
how protein noise - the variability among identical cells in the number
of protein molecules for a given gene - influences genome stability.
Identification of Chemical Mode
of Action
Chemicals identified by phenotypic screening
are valuable genetic tools to study complex cellular process and are often
attractive candidates for drug development. Identification of the mechanism
of action or target of these chemicals is critical for evaluating and optimizing
therapeutic agents. The Baetz laboratory exploits the cross-species conservation
of biochemical pathway function between yeast and human cells to gain insights
into the mode of action of various compounds. In particular the laboratory
is performing cell-based robotic screening procedures with the yeast deletion
mutant arrays to discover drug targets or mode of action.
Copyright © 2006 Baetz Lab, All rights reserved.