Catherine A. Fox
Credentials: Conservation and diversity in mechanisms that control the inheritance and expression of eukaryotic chromosomes
Position title: Professor
Phone: (608) 262-9370
5204C Biochemical Sciences Building
440 Henry Mall, Madison, WI 53706
- B.S. 1986, University of California-Riverside
- Ph.D. 1992, University of Wisconsin-Madison (M. Wickens)
- Postdoctoral 1992-96, University of California-Berkeley (J. Rine)
Honors & Awards
1996 Burroughs-Wellcome Career Development Award in the Biomedical Sciences
Junior faculty award from the Howard Hughes Medical Institute Research Resources Program for Medical Schools.
1998 Shaw Scientist Award
1999 Pilot project award from the Howard Hughes Medical Institute Research Resources Program for Medical Schools
2002 American Cancer Society Research Scholar
2005 Vilas Associate Award from the Graduate School, UW Madison
2007 Vilas Life Cycle Award
2014 UW-Madison Teaching & Learning Innovation Award for Team Origin, an undergraduate research program in the Fox lab
2016 Vilas Life Cycle Award
2016 Member, Faculty of 1000 (now Faculty Opinions)
2018 Fellow of the American Academy of Microbiology
Our lab wants to understand how different types of chromatin structures have an impact on genome duplication and stability in eukaryotic cells. We use budding yeast (Saccharomyces cerevisiae) as our model organism for many reasons. First, many biochemical and genetic experiments that have defined the mechanisms of genome duplication have been performed in this model organism, providing us with a wealth of knowledge and tools to perform hypothesis-driven experiments in a cellular context. Second, budding yeast are an exceptionally tractable model organism where biochemical, molecular, genetic, microbiological and genomic approaches can be combined to test sophisticated models. Third, because the basic processes we study are well conserved, what we learn in yeast guides the experiments and interpretations from research in more complex eukaryotic organisms. This last point is important because genome duplication and stability are critical for normal cell proliferation and differentiation in multicellular organisms, including humans. Alterations in genome duplication programs, as well as the associated defects in genome stability, are hallmarks of both normal aging and cancerous cells.
DNA replication origins (origins) are a major interest. Origins are the positions on chromosomes where the chromosomal DNA is unwound to allow for new DNA synthesis. Origin winding is the first step of genome duplication and is therefore highly regulated. In eukaryotic cells, this step is tightly coupled to the cell cycle. In G1-phase, multiple proteins and protein complexes, including the Origin Recognition Complex (ORC), work together to load the replicative helicase complex, called the MCM complex. The MCM complex is loaded as an inert double-hexamer containing two hexameric helicases. Only in S-phase is the MCM complex activated and converted into the two active MCM helicases. This activation triggers origin unwinding and the two active helicase holoenzymes, now each encircling single-stranded DNA, will continue to unwind the parental DNA helix for new DNA synthesis. While these basic biochemical steps are now fairly well understood, the field has a comparatively poor understanding of how these steps contend with or are regulated by the complex chromatin structures that that exist in cells. This issue is important because in eukaryotic cells, each chromosome relies on many individual origins physically distributed across its length for its efficient and accurate duplication. Because chromatin structures vary considerably across a chromosome’s length, this fact means that the basic origin machinery must contend with a variety of different chromatin structures. How the core protein-protein and protein-DNA interactions involving the core replication machinery adapt to work in different chromatin environments is unknown.
We are using genetic, genomic and biochemical approaches to define the different chromatin structures that affect the steps required for origin function. We have defined chromatin features that promote the binding of the Origin Recognition Complex (ORC) to DNA, as well as the subsequent loading of the MCM complex in G1. We have also defined chromatin features that can inhibit these steps. We are trying to understand how the various modes of chromatin regulation work with the basic core replication machinery to insure that chromosomes are efficiently and accurately duplicated during cell division.
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- Ling, X., Z. Jin, Q. Jiang, X. Wang, B. Wei, Z. Wang, Y. Xu, T. Ca, J.W. Engle, W. Cai, C. Su, and Q. He. (2021). Engineering biocompatible TeSe nano-alloys as a versatile theranostic nanoplatform. National science review, 8: .