Werner syndrome (WS) is a premature aging disorder characterized by genomic instability. The defects observed in WS cells may result from the inability to resolve alternate DNA structures. One hypothesis is that WRN and other RecQ helicases function to resolve structures that impede progression of the replication fork. Replication defects observed in WS are consistent with this notion. Recently we have shown that WRN unwinds a number of alternate structures including triplexes, tetraplexes, and Holliday junctions. The cellular defects and genomic instability of WS may arise from persistent DNA structures that fail to be resolved by certain RecQ helicases. We are currently defining the DNA substrate requirements for efficient DNA unwinding by WRN and the effects of DNA modifications on WRN catalytic activity. This work will provide insight to the action of WRN on DNA structures that arise during replication or repair. To understand the molecular functions of DNA helicases, we are interested in protein interactions of WRN. Defining the protein interactions of WRN will help to elucidate cellular processes to maintain genome integrity. Our studies have demonstrated that WRN physically an dfunctionally interacts with a number of important proteins that include RPA, Ku, and p53. These interactions modulate the catalytic activities of WRN, and are likely to be important in DNA metabolic pathways that confer genome stability. Recently we demonstrated that WRN physically interacts the structure-specific nuclease human flap endonuclease 1 (FEN-1) and dramatically stimulates its cleavage activity. We are presently exploring mechanistic aspects of the WRN-FEN-1 interaction and the functional importance of the WRN-FEN-1 interaction in vivo. Ongoing studies in this area will hopefully shed light on the potential importance of the WRN-FEN-1 interaction on genome stability that is perturbed in WS.
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