EXCEED THE SPACE PROVIDED Goals The repair of double-strand DNA breaks will be studied in Drosophila This work is aimed at determining what factors influence the cell's 'choice' of which of several repair pathways to utilize These pathways lead to different final products of repaired DNA The factors to be examined are Genomic position of break Presence of DNA repair mutations Age of the mganism and timing of the DNA break The existence of a large number of breaks m the cell Genetic 'master switches' that affect gene expression Methods A system has been developed whereby double-strand breaks are made in the Drosophila germline, and the relative usage of four alternative pathways can be ascertained DNA breakage occurs at a particular site within a specially constructed transposable genetic element named Rreporterl The element is designed in such a way that the different repair pathways lead to genetically distinguishable products To determine the effect of genomic position, the R] eporterl element is noved to a variety of sites within the Drosophila genome, and the relative usage of the four repmr pathways is ascertained for each position Fol the other variables, the positions of Rreporter 1 are fixed, while changes in the genetic backgl ound, age of the individual, or environmental vmiables are tested for their effects on pathway usage Medical Significance DNA repair is recogl]ized as c] ucial to maintaining the stability of the genome, especially in species with complex genomes Human mutations in many DNA repair genes, including the human homologs of several of the loci in the present study, cause predisposition to cancer Some of the repair pathways produce primarily faithful repair ploducts, but others are highly error-prone Thus, the choice of pathway can be critical for cancer protection PERFORMANCE SITE ========================================Section End===========================================
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