The Werner Syndrome (WS) is a rare human genetic disease with many features of premature aging. It has been considered by many researchers as a useful model for human aging studies. The gene that caused WS phenotype has recently been cloned and was named WRN. It encodes a protein homologous to RecQ family of helicases. Indeed, the recombinant WRN protein produced using baculovirus expression system contains a DNA helicase activity as well as an exonuclease activity. Interestingly, analysis of different WS patients suggests that some WRN mutations may impair the interactions between WRN and other proteins. This raised a possibility that WRN functions within a multisubunit protein complex in vivo. We have now successfully purified one such complex and identified all its subunits by microsequencing. The WRNp partners within the complex are all involved in repair of DNA damage and in signaling pathways leading to cell cycle arrest and cell death. Our data suggest that the defects in WS patients are caused by ineffient repair of a specific type of DNA damage and by inadequate activation of the cell response pathways to the damage. We have characterized the biochemical properties of this complex and have found it possesses multiple enzymatic activities, many of which are distinctive from the individual components. Characterization of this complex will be crucial for our understanding of how WRN functions, as well as how mutations in WRN cause the premature aging phenotype in WS patients.
