Loss of the Werners Syndrome exonuclease sensitizes flies to replication stress and promotes tumorigenesis. Mitch McVey¹, Elyse Bolterstein¹, Rachel Rivero¹, Robert Salomon². 1) Tufts University, Medford, MA; 2) Tufts Medical Center, Boston, MA.

   Werners Syndrome (WS) is an autosomal recessive disease that causes accelerated aging and increased susceptibility to cancer in affected patients. WS is caused by mutations in WRN, a member of the RecQ family of helicases that contains both a helicase and exonuclease domain and plays critical roles in DNA replication, repair, and the maintenance of genome integrity. The Drosophila melanogaster homolog, WRNexo, consists of only the exonuclease portion of WRN, which provides a unique opportunity to study the exonuclease functions in DNA repair separate from the helicase. We have created a wrnexo null mutant in which the entire gene locus is deleted. Flies lacking Wrnexo are not sensitive to the topoisomerase I inhibitor camptothecin or to the double-strand break-inducing agent bleomycin, but are sensitive to hydroxyurea. This suggests that Wrnexo may be important for resolving stalled replication forks but not for repair of two-ended breaks. Furthermore, wrnexo mutant embryos have reduced hatch rates and display defects during nuclear divisions in early embryogenesis, consistent with a role for Wrnexo under conditions of high replicative stress. Finally, we have observed that wrnexo mutants have increased frequencies of tumor formation in their testes, similar to what is observed in flies lacking the RecQ helicase DmBlm. Currently, we are attempting to determine whether Wrnexo and DmBlm act together or separately during various DNA replication and repair processes. Our ultimate goal is to characterize the division of labor between RecQ orthologs in various organisms.