Werner syndrome exonuclease catalyzes structure-dependent degradation of DNA

Werner syndrome (WS) is an autosomal recessive disease characterized by ear ly 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 activ ity. Currently, WRN is the only member of the widely distributed RecQ DNA h elicase family with documented exonuclease activity. It is not known whethe r deficiency of the exonuclease or helicase/ ATPase activities of WRN, or a ll of them, is responsible for various elements of the WS phenotype, WRN ex onuclease has limited homology to Escherichia coli RNaseD, a tRNA processin g enzyme. We show here that WRN preferentially degrades synthetic DNA subst rates containing alternate secondary structures, with an exonucleolytic mod e of action suggestive of RNaseD. We present evidence that structure-depend ent binding of WRN to DNA requires ATP binding, while DNA degradation requi res ATP hydrolysis. Apparently, the exonuclease and ATPase act in concert t o 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.