What do we want to know? 
How are the earliest steps in DNA replication controlled, and how might disruptions in that control affect genome stability and cancer?  How do signaling pathways that control cell cycle progression  (both intracellular and extracellular) interface with DNA replication control?  Follow the link for “Research” to read more background.

Why do we care? 
We are intensely curious about how thousands of replication initiation sites (origins) are coordinately regulated so that they initiate efficiently, but only once per cell cycle.  We wonder how cells manage to ensure that replication doesn’t occur under inappropriate circumstances, such as when the DNA is damaged. It's becoming increasingly clear that cancer cells initiate replication inappropriately and furthermore, that they do a pretty "sloppy" job of precisely duplicating their genomes once they get started. We want to know how replication should be controlled and how that control is disrupted in cancer cells.

How do we figure it out? 
We use a combination of biochemistry, cell biology, molecular biology, pharmacology, and genetics.  We grow mammalian cells in culture (both cancer cell lines and normal cells) and manipulate the replication initiation factors and signaling activities in those cells.  We suppress expression of replication and signaling proteins with siRNA “knockdown,” inhibit enzyme activities with drugs, or overproduce proteins by transient transfection, retroviral insertion, or adenoviral infection.  We measure protein abundance, chromatin localization, cell cycle progression, replication activity, protein-protein interactions, etc… In some cases we use the budding yeast Saccharomyces cerevisiae for our experiments because it is genetically tractable, and all the replication origins are known (unlike human cells). We have active collaborations with many other cell cycle and DNA metabolism labs both at UNC and at other institutions.

What have we learned so far? 
We discovered the mechanism of Cdc6 ubiquitination and degradation after DNA damage.  We identified the ubiquitin ligase responsible for Cdc6 regulation during a DNA damage response (Hall et al 2007).  Follow the link for “Publications” to run an automatic search for all the lab’s papers in PubMed.

We've also recently submitted papers describing a new cell cycle checkpoint (Nevis et al.), a sensitive method to detect rereplication (Dorn et al.), and a mechanism to restrain rereplication once it begins (Hall et al.).