Modeling Werner Syndromein Drosophila melanogaster Hyper-recombination in Flies LackingWRN-like Exonuclease

摘要

Human progeroid Werner syndrome provides the currentbest model for analysis of human aging, recapitulating many aspects ofnormal aging as a result of mutation of the WRN gene. This gene en-codes a RecQ-type helicase with additional exonuclease activity. Whilebiochemical studies in vitro have proven invaluable in determining sub-strate specificities of the WRN exonuclease and helicase, it has been diffi-cult to dissociate the two key enzyme activities in vivo. We are developingDrosophila as a model system for analysis of WRN function; the suitabil-ity of Drosophila for extensive and sophisticated genetic manipulationpermits us to investigate regulatory pathways and the impact of WRNloss at organismal, cellular, and molecular levels. BLASTP screening ofthe Drosophila genome with human WRN sequence allowed us to identifythree RecQ helicases with strong homology to human WRN, a presumedhelicase component of the spliceosome, and two DEAH-box putative RNAhelicases with weaker WRN homology. None of these helicases containa WRN-like exonuclease domain, but two potential WRN-like exonucle-ases in flies encoded by the loci CG7670 and CG6744 were also identifiedin the BLAST search. CG6744 and CG7670 are more closely related tohuman WRN than to each other. We have obtained a fly strain with apiggyBac insertional mutation within the CG6744 locus, which decreasesexpression of the encoded mRNA. Such flies show elevated levels of so-matic recombination. We suggest that WRN-like exonuclease activity iscritical in maintaining genomic integrity in flies.