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 involved in WS 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 a 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 the possibility that WRN functions within a multisubunit protein complex in vivo. We have 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 inefficient repair of a specific type of DNA damage and by inadequate activation of cell response pathways to that damage. We have characterized the biochemical properties of this complex and have found that it possesses multiple enzymatic activities, many of which are distinct from what the isolated individual components do. In addition, we have recently identified other forms of the WRN complex, which appear to contain more partners. We have identified several of these and are planning to identify the remaining ones to look for more clues for WRN function.
