Werner syndrome protein interacts with human flap endonuclease 1 and stimulates its cleavage activity

Werner syndrome (WS) is a human premature aging disorder characterized by c hromosomal instability. The cellular defects of WS presumably reflect compr omised or aberrant function of a DNA metabolic pathway that under normal ci rcumstances confers stability to the genome. We report a novel interaction of the WRN gene product with the human 5' flap endonuclease/5'-3' exonuclea se (FEN-1), a DNA structure-specific nuclease implicated in DNA replication , recombination and repair. WS protein (WRN) dramatically stimulates the ra te of FEN-1 cleavage of a 5' flap DNA substrate. The WRN-FEN-1 functional i nteraction is independent of WRN catalytic function and mediated by a 144 a mino acid domain of WRN that shares homology with RecQ DNA helicases. A phy sical interaction between WRN and FEN-1 is demonstrated by their co-immunop recipitation from HeLa cell lysate and affinity pull-down experiments using a recombinant C-terminal fragment of WRN. The underlying defect of WS is d iscussed in light of the evidence for the interaction between WRN and FEN-1 .