5204C Biochemical Sciences Building
440 Henry Mall
Madison WI 53706
Phone: (608) 262-9370
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)
Burroughs Wellcome Career Award in Biomedical Sciences, 1996
Shaw Scientist Award, 1998
American Cancer Society Research Scholar, 2002
Vilas Associate Award from the Graduate School, UW-Madison 2005-2007
Our lab examines processes that occur in the nucleus, the "command center" of the eukaryotic cell. A focus is on mechanisms that regulate chromosome replication and genome stability, as well as how these processes are coordinated with chromatin structural changes and transcription to allow cells to grow and divide normally. These are fundamental questions in chromosome biology with high relevance to human development and disease. We use Saccharomyces cerevisiae (budding yeast) as a model because while the basic mechanisms we study are conserved in all eukaryotic cells, yeast let us apply a vast array of experimental approaches including molecular biology, classical and reverse genetics, genomics, cell biology and biochemistry to address our questions
A current focus is on the structure and function of eukaryotic DNA replication origins, the sites where chromosomal replication begins. Most undergraduates learn about DNA replication based on studies from E. coli, a prokaryotic model organism. While the most basic aspects of mechanism are conserved, the regulation of DNA replication is much different in eukaryotic cells, and fundamental questions remain concerning the selection and function of DNA replication origins and the impact of chromatin structure and cell cycle regulators on these processes. In addition, eukaryotic chromosomes require the action of many origins per cell division; reductions in origin number can delay the cell cycle and cause genome instability that leads to cancer and other diseases. Moreover, individual origins vary in their efficiency and time of activation during S-phase, creating a distinct temporal pattern of genome duplication (Fig.1) that is also important for genome stability and coordinating chromosome replication with other functions critical for cell division such as chromosome segregation. In multicellular organisms, the resulting origin-determined genome replication pattern shows cell-type specificity and is associated strongly with normal cell differentiation and proliferation. For certain types of human cells, changes in the normal replication-timing program may serve as an early marker for cancer. Therefore, the centrality of DNA replication origins to normal eukaryotic cell proliferation and genome stability is abundantly clear. However, we have only a limited understanding of how origins are specified (origin selection in G1-phase) or controlled (regulated at the level of function in S-phase) within chromatin. Understanding chromatin-mediated control of origin selection and function will inform efforts to enhance cell proliferation for tissue regeneration or inhibit it to control growth of cancer cells or eukaryotic pathogens.
We are pursing several projects to define the DNA-sequence elements and chromatin components necessary for the selection of DNA replication origins by the conserved initiator complex called ORC (for origin recognition complex). We are particularly interested in defining how ORC interacts with chromatin at origins. We have projects that use genome-wide, classical genetic and/or direct biochemical (with our colleague, Professor John Denu in Biomolecular Chemistry) approaches. Recent data from our lab have led to an exciting idea about how the origin-selection step in G1-phase may regulate origin function (i.e. origin firing; DNA replication initiation) in S-phase, and we are adapting a synthetic chromosome to test these ideas using genetic, molecular and single-molecule approaches (with our colleague, Assistant Professor Aaron Hoskins in Biochemistry). We are also interested in exploring a new connection between chromosome structure and replication and the inner nuclear membrane that depends on palmitoylation, a fatty acid modification that we recently discovered has unanticipated and thus completely unexplored roles in the nucleus.
Perform a customized PubMed literature search for Dr. Fox.
• Hoggard T, Shor E, Müller CA, Nieduszynski CA, Fox CA. A Link between
ORC-origin binding mechanisms and origin activation time revealed in budding
yeast. PLoS Genet. 2013;9(9):e1003798. doi: 10.1371/journal.pgen.1003798. Epub
2013 Sep 12. PubMed PMID: 24068963; PubMed Central PMCID: PMC3772097.
• Shor E, Fox CA, Broach JR. The yeast environmental stress response regulates
mutagenesis induced by proteotoxic stress. PLoS Genet. 2013;9(8):e1003680. doi:
10.1371/journal.pgen.1003680. Epub 2013 Aug 1. PubMed PMID: 23935537; PubMed
Central PMCID: PMC3731204.
• Park S, Patterson EE, Cobb J, Audhya A, Gartenberg MR, Fox CA. Palmitoylation
controls the dynamics of budding-yeast heterochromatin via the telomere-binding
protein Rif1. Proc Natl Acad Sci U S A. 2011 Aug 30;108(35):14572-7. doi:
10.1073/pnas.1105262108. Epub 2011 Aug 15. PubMed PMID: 21844336; PubMed Central
• Chang F, May CD, Hoggard T, Miller J, Fox CA, Weinreich M. High-resolution
analysis of four efficient yeast replication origins reveals new insights into
the ORC and putative MCM binding elements. Nucleic Acids Res. 2011
Aug;39(15):6523-35. doi: 10.1093/nar/gkr301. Epub 2011 May 9. PubMed PMID:
21558171; PubMed Central PMCID: PMC3159467.
• Müller P, Park S, Shor E, Huebert DJ, Warren CL, Ansari AZ, Weinreich M, Eaton
ML, MacAlpine DM, Fox CA. The conserved bromo-adjacent homology domain of yeast
Orc1 functions in the selection of DNA replication origins within chromatin.
Genes Dev. 2010 Jul 1;24(13):1418-33. doi: 10.1101/gad.1906410. PubMed PMID:
20595233; PubMed Central PMCID: PMC2895200.
• 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, Fox CA. The
origin recognition complex interacts with a subset of metabolic genes tightly
linked to origins of replication. PLoS Genet. 2009 Dec;5(12):e1000755. doi:
10.1371/journal.pgen.1000755. Epub 2009 Dec 4. PubMed PMID: 19997491; PubMed
Central PMCID: PMC2778871.
• Hou Z, Danzer JR, Mendoza L, Bose ME, Müller U, Williams B, Fox CA.
Phylogenetic conservation and homology modeling help reveal a novel domain within
the budding yeast heterochromatin protein Sir1. Mol Cell Biol. 2009
Feb;29(3):687-702. doi: 10.1128/MCB.00202-08. Epub 2008 Nov 24. PubMed PMID:
19029247; PubMed Central PMCID: PMC2630688.
• Fox CA, Weinreich M. Beyond heterochromatin: SIR2 inhibits the initiation of
DNA replication. Cell Cycle. 2008 Nov 1;7(21):3330-4. Epub 2008 Nov 10. PubMed
• Patterson EE, Fox CA. The Ku complex in silencing the cryptic mating-type
loci of Saccharomyces cerevisiae. Genetics. 2008 Oct;180(2):771-83. doi:
10.1534/genetics.108.091710. Epub 2008 Aug 20. PubMed PMID: 18716325; PubMed
Central PMCID: PMC2567379.
• Casey L, Patterson EE, Müller U, Fox CA. Conversion of a replication origin
to a silencer through a pathway shared by a Forkhead transcription factor and an
S phase cyclin. Mol Biol Cell. 2008 Feb;19(2):608-22. Epub 2007 Nov 28. PubMed
PMID: 18045995; PubMed Central PMCID: PMC2230585.
• Hou Z, Danzer JR, Fox CA, Keck JL. Structure of the Sir3 protein bromo
adjacent homology (BAH) domain from S. cerevisiae at 1.95 A resolution. Protein
Sci. 2006 May;15(5):1182-6. PubMed PMID: 16641491; PubMed Central PMCID:
• Gabrielse C, Miller CT, McConnell KH, DeWard A, Fox CA, Weinreich M. A Dbf4p
BRCA1 C-terminal-like domain required for the response to replication fork arrest
in budding yeast. Genetics. 2006 Jun;173(2):541-55. Epub 2006 Mar 17. PubMed
PMID: 16547092; PubMed Central PMCID: PMC1526507.
• McConnell KH, Müller P, Fox CA. Tolerance of Sir1p/origin recognition
complex-dependent silencing for enhanced origin firing at HMRa. Mol Cell Biol.
2006 Mar;26(5):1955-66. PubMed PMID: 16479013; PubMed Central PMCID: PMC1430255.