Wold, Marc, Ph.D.

Marc Wold
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Molecular mechanisms of eukaryotic chromosomal DNA replication and repair; biochemistry of eukaryotic replication proteins; eukaryotic single-strand DNA-binding proteins

In order to grow, a human cell must precisely duplicate the entire genome each cell cycle and continuously protect it from damage or modification. Defects in cellular DNA metabolism have a direct role in many human disease processes including cancer, trinucleotide repeat diseases such as Fragile X and Huntington’s diseases, and genetic diseases such as Xeroderma Pigmentosum, Cockayne’s and Werner’s syndromes. Furthermore, accumulation of genomic mutations is thought to be a major contributor to cellular aging. Replication protein A (RPA) is a multi-functional, single-stranded DNA-binding protein that is essential for DNA replication, DNA repair, recombination and the cell’s response to DNA damage. The RPA complex is composed of three subunits, RPA1, RPA2 and RPA3 that contain a total of six essential, structurally conserved DNA-binding domains. The cellular functions of these domains remain poorly understood. Normal human tissues also contain an alternative RPA complex (aRPA) in which the RPA2 subunit is replaced by the novel isoform RPA4. aRPA is present in normal tissues but down-regulated in cancer cells. Functionally, aRPA supports DNA repair and recombination but does not support chromosomal DNA replication. We are utilizing a combination of functional studies in cells and biochemical analysis to understand the unique, essential cellular functions the two cellular RPA complexes, RPA and aRPA. These studies will focus on the interactions of individual domains of RPA with the different DNA substrates and protein complexes that arise during DNA replication, repair and recombination. These studies will also determine whether cellular levels of aRNA can modulate cell proliferation and whether aRPA will serve as target for novel therapeutic agents. We are also analyzing several classes of RPA mutants that function in DNA replication but have defects in DNA repair and checkpoint activation. These studies will define the functions of RPA unique to DNA repair. These studies will lead to a better understanding of the molecular mechanisms of cellular DNA metabolism in both non-proliferating and proliferating cells.

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