title: Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA.
abstract: Werner syndrome (WS) is an autosomal recessive disease characterized by early onset of many features of aging, by an unusual spectrum of cancers, and by genomic instability. The WS protein (WRN) possesses 3'-->5' DNA helicase and associated ATPase activities, as well as 3'-->5' DNA exonuclease activity. Currently, WRN is the only member of the widely distributed RecQ DNA helicase family with documented exonuclease activity. It is not known whether deficiency of the exonuclease or helicase/ATPase activities of WRN, or all of them, is responsible for various elements of the WS phenotype. WRN exonuclease has limited homology to Escherichia coli RNaseD, a tRNA processing enzyme. We show here that WRN preferentially degrades synthetic DNA substrates containing alternate secondary structures, with an exonucleolytic mode of action suggestive of RNaseD. We present evidence that structure-dependent binding of WRN to DNA requires ATP binding, while DNA degradation requires ATP hydrolysis. Apparently, the exonuclease and ATPase act in concert to catalyze structure-dependent DNA degradation. We propose that WRN protein functions as a DNA processing enzyme in resolving aberrant DNA structures via both exonuclease and helicase activities.
authors.affiliation: Department of Pathology, Box 357705, University of Washington, Seattle, WA 98195-7705, USA.
authors.forename: J C
authors.initials: JC
authors.lastname: Shen
authors.forename: L A
authors.initials: LA
authors.lastname: Loeb
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D004247:DNA / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D004265:DNA Helicases / Q000378:metabolism*; D004277:DNA, Single-Stranded / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004789:Enzyme Activation; D005090:Exodeoxyribonucleases; D005092:Exonucleases / Q000378:metabolism*; D006801:Humans; D009690:Nucleic Acid Conformation; D053484:RecQ Helicases; D013379:Substrate Specificity; D013698:Templates, Genetic; D014898:Werner Syndrome / Q000201:enzymology*; D000071657:Werner Syndrome Helicase
chemical_list: D004277:DNA, Single-Stranded; D000255:Adenosine Triphosphate; D004247:DNA; D005090:Exodeoxyribonucleases; D005092:Exonucleases; D000251:Adenosine Triphosphatases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase