) In a variety of organisms, mutations that cause depletion of DNA replication enzymes increase the incidence of genetic instability-- events that are characterized by elevated rates of recombination deletion, and/or chromosome loss. Many of the cellular phenotypes of Werner Syndrome (WS) suggest that it falls into this class of genetic defect. The Werner syndrome gene WRN was recently cloned and sequenced and was found to encode a DNA helicase of the RecQ family. The applicants propose that cells that carry out replication in the absence of the WRN helicase leave behind lesions in the DNA that are repaired by a recombination system that produces the genomic rearrangements. They plan to explore this possibility in yeast, by looking for specific types of replication defects that might be generated in the absence of the yeast WRN helicase homologue, Sgs1p. In addition, by studying the types of recombination events induced in yeast cells deficient for the Sgs1 protein, and by looking for proteins that interact with both the normal WRN and Sgs1 helicases, they hope to gain insight into the types of primary damage generated by the replication machinery in the absence of this helicase. The identification of yeast proteins with homology to human proteins and the ability to study them genetically in yeast has led to an understanding of many processes that contribute to human disease. Because of the small genome size of S. cerevisiae-- recently sequenced in its entirety-- the physical analysis of chromosomes during their replication is quite feasible. In no other eukaryotic organism have the cis-acting elements and trans-acting proteins for replication initiation been as well characterized as they have been in yeast. Moreover, the ease with which the genome can be manipulated makes yeast an ideal host organism in which to study basic chromosome biology. Finally, yeast provides a user-friendly cellular environment in which to study protein-protein interactions by way of the two-hybrid transcriptional reporter system.
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