Address: 5204C Biochemical Sciences Bldg
Department: Biomolecular Chemistry
Research InterestsMechanisms required for genome duplication and stability in eukaryotic organisms
Research FieldsCell Biology
Genomics & Proteomics
We pursue studies of eukaryotic
chromosomes and associated regulatory proteins in budding yeast
Saccharomyces cerevisiae as a model organism. We are interested in
mechanisms that regulate chromosome replication, genome stability and
gene expression in eukaryotic cells, as well as the mechanisms by which
cells coordinate and integrate these processes in order to grow and
divide normally. These are fundamental biological questions relevant to
both human disease, particularly cancer, and development.
Eukaryotic DNA replication origins: DNA replication origins are the specific positions on chromosomes where DNA replication begins (initiates). DNA replication initiation (origin firing) is a major regulated step of cell division and it must occur precisely and at the correct time in a cell’s life cycle. Most undergraduate students learn about DNA replication in prokaryotic organisms like E.coli where we know much more. Far less is known about eukaryotic DNA replication. In fact, we do not know where most DNA replication origins occur in metazoan chromosomes, including humans. Yeast is a powerful model eukaryote for studying the chromosomal forces that help establish, or limit, the formation of DNA replications origins.
Eukaryotic chromosomes, in contrast to E.coli, rely on multiple origins for DNA replication, even the small chromosomes of yeast. Each yeast chromosome (there are 16 nuclear chromosomes) is smaller than the E.coli genome that uses only a single replication origin for its complete duplication, yet each contains between 10-20 active replication origins!! Why do eukaryotic genomes contain so many replication origins? Why do origins show so much variation in terms of efficiency of initiation or time of initiation during S-phase? What are the mechanistic causes of this variation? What kind of evolutionary pressure/selection mechanisms act on individual origins? This is an interesting question since it appears eukaryotic cells have many more origins necessary for efficient cell division. How does the efficiency of origin use influence genome stability? These are some of the questions we are addressing on this subject.
Cell cycle regulators and chromatin/chromosome architecture and dynamics: Eukaryotic chromosomes are packaged into chromatin, and specific chromatin structures (i.e. the particular combination of post-translational modifications on histones and non-histone chromosome binding proteins) vary considerably over the length of even a single chromosome. In addition, the chromosome adapts a specific 3-dimensional architecture in the nucleus with respect to other chromosomes and the nuclear membrane. This architecture can influence chromatin structure and the functions of chromosomes, but it is unclear how. In addition, chromosomal architecture is dynamic (and must be!) to accommodate the changes chromosomes must undergo during the cell cycle. We have several different projects that are focused on cell cycle and chromatin regulators conserved from yeast to humans. We are pursuing the function of these regulators using a variety of experimental approaches.
We take a multidisciplinary approach to these complex, fundamental questions of chromosome biology that includes: classical and molecular genetics, genomics, bioinformatics/computational biology, biochemistry and cell biology.
Casey L, Patterson EE, Müller U and CA Fox. 2008. Conversion
of a replication origin to a silencer through a pathway shared by FKH1 and CLB5. Mol. Biol. Cell. 19: 608-22. PMID: 18045995
Patterson EE and CA Fox. 2008. The Ku complex in silencing the cryptic mating-type loci of Saccharomyces cerevisiae. Genetics 180: 771-783. PMID: 18716325
Fox CA and M Weinreich 2008. Beyond heterochromatin: SIR2 inhibits the initiation of DNA replication. Cell Cycle 7: 3330-3334. PMID 18948737
Hou Z, Danzer JR, Mendoza L, Bose ME, Müller U, Williams B and CA Fox. 2009. Phylogenetic conservation and homology modeling help reveal a novel domain within the budding yeast heterochromatin protein Sir1. Mol Cell Biol. 29: 687-702. PMID: 19029247
Shor E, Warren CL, Tietjen J, Hou Z, Müller U, Alborelli I, Gohard FH, Yemm AI, Borisov L, Broach JR, Weinreich M, Nieduszynski CA, Ansari AZ and CA Fox. 2009. The origin recognition complex interacts with a subset of metabolic genes tightly linked to origins of replication. PLoS Genetics 5: e1000755. PMID: 19997491
Müller P, Park S, Shor E, Huebert DJ, Warren CL, Ansari AZ, Weinreich M, Eaton M, MacAlpine DM and CA Fox. 2010. The conserved bromo-adjacent homology domain of yeast Orc1 functions in the selection of DNA replication origins within chromatin. Genes & Dev. 24: 1418-1433. PMID: 20595233
Park S, Patterson EE, Cobb J, Audhya A, Gartenberg MR, and CA Fox. 2011. Palmitoylation controls the dynamics of budding yeast heterochromatin via the telomere-binding protein Rif1. Proc. Natl. Acad. Sci. 108: 14572-14577. PMID: 21844336
Chang F, May CD, Hoggard T, Miller J, Fox CA and M. Weinreich. 2011. High-resolution analysis of four efficient yeast replication origins reveals new insights into the ORC and putative MCM binding elements. Nucleic Acids Research. 39: 6523-35. PMID: 21558171
Fox CA and MR Gartenberg. 2012. Palmitoylation in the Nucleus: A Little Fat around the Edges. Nucleus 3: 251-255. PMID: 21844336