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Judith L. Campbell
Professor of Chemistry and Biology

The Campbell group studies DNA replication in the yeast Saccharomyces cerevisiae. Yeast offers an as yet unparalleled ability to combine genetic, molecular, and biochemical approaches in a eukaryotic organism. In the past, biochemistry has focused on the characterization of individual proteins. In modern biochemistry, the emphasis is on studying protein/protein interactions in multienzyme assemblies. In keeping with this trend, the overall goal is to reproduce the assembly and activation of the replication fork at an origin of replication using purified proteins. Work in preparation for achieving this goal has ranged from defining the structure and activity of chromosomal replication origins, to the discovery of replicative enzymes, verification of their in vivo roles using yeast genetics, and the detailed characterization of their enzymatic mechanisms.

While it goes without saying that the DNA polymerases are of central importance in DNA replication, the large number of polymerases required for eukaryotic DNA replication, at least five, has stymied efforts to define the individual roles. Based on discoveries in the lab over the last three years, the Campbell group is proposing that the most important function of one of the polymerases, DNA polymerase epsilon, is to interact with a newly discovered DNA polymerase, pol kappa, which is required to link DNA replication to sister chromatid cohesion. Pol epsilon appears to recruit an auxilliary apparatus, including but not limited to pol kappa, that replicates the specific sites of the DNA where the cohesin proteins mediate physical links between daughter chromosomes.

DNA helicases provide the second most important catalytic activity in DNA replication. Several years ago we identified one essential DNA helicase, Dna2 helicase. As with the DNA polymerases, there are multiple helicases involved in DNA replication, and the group is occupied with teasing out their individual roles. The group first demonstrated that Dna2 is involved in processing of Okazaki fragments during DNA replication.
More important, Professor Campbell's group has studied the role of this protein in the preservation of genome stability. DNA replication is not a continuous process. Due to various blocks, DNA replication forks stall and collapse and must be reassembled to complete each cell cycle. Dna2 may be involved in such reassembly. The group's recent results has led them to pursue a model that suggests that Dna2 may be a functional homolog of the human Werner syndrome protein, mutations in which cause many symptoms of premature aging and cancer predisposition. Indeed, dna2 mutants of yeast, show premature aging and severe genomic instability as a function of age.