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SEMINAR: Catherine Fox, PhD (Univ. of Wisconsin)
December 5, 2017 @ 11:00 am - 12:00 pm
Catherine Fox, PhD, Professor, Univ. of Wisconsin, Department of Biomolecular Chemistry
Host: Jean Cook, PhD
The field of eukaryotic DNA replication has made great progress in defining the reactions that establish a DNA replication origin, the chromosomal position where the parental DNA is unwound for new DNA synthesis (origin function/activation). A protein complex named ORC must bind to DNA and, in G1-phase, interact with a protein called Cdc6 to direct the association of a replicative helicase complex, Cdt1-MCM, to ultimately form a double hexamer of two helicase complexes (dhMCM) encircling dsDNA. In S-phase, the dhMCM is remodeled by S-phase kinases and accessory factors into two active MCM helicases that encircle ssDNA and unwind parental DNA, causing origin activation. While these reactions have been reconstituted in vitro with purified proteins such that deeper mechanistic questions can be addressed, the field has an incomplete view of how they occur within and are regulated by chromatin. A major challenge is that chromatin shows heterogeneity, varying in structural characteristics across the length of a chromosome, and every chromosome needs multiple independent origins distributed across its length for its replication. Thus the individual reactions required for DNA replication origin function must occur within many different chromatin contexts, but we do not yet really understand the chromatin environments that individual origins can exploit or must contend with. Moreover, each origin is unique in terms of how often (efficiency) and when (activation time) it functions in S-phase, establishing a diversity of origin function across the genome essential for normal cell proliferation and genome stability. It is unclear what mechanistic steps of origin function affected by chromatin are impinging on this temporal diversity of origin activation. My lab is addressing the role of chromatin context in the G1-phase reactions. I will discuss recent unpublished work focused on efforts to define specific chromatin-associated factors that influence binding of ORC to DNA and the loading of the dhMCM helicase. A lot of the work I plan to discuss is unpublished, but here are some papers to provide some background knowledge:
To appreciate some results discussed in the seminar, this paper might serve as decent background.
Hoggard T, Shor E, Muller CA, Nieduszynski CA, and CA Fox, 2013. A link between ORC-ˇorigin binding
mechanisms and origin activation time revealed in budding yeast. PLoS Genetics 9:e10033798. PMCID:PMC3772097
To appreciate another aspect of the seminar, this older review might help. I will discuss recent results that build on this older work.
Catherine A. Fox & Michael Weinreich (2008) Beyond heterochromatin: SIR2
inhibits the initiation of DNA replication, Cell Cycle, 7:21, 3330-3334, DOI: 10.4161/cc.7.21.6971