Werner's syndrome protein is required for correct recovery after replication arrest and DNA damage induced in S-phase of cell cycle

Werner's syndrome (WS) is a rare autosomal recessive disorder that arises a s a consequence of mutations in a gene coding for a protein that is a membe r of RecQ family of DNA helicases, WRN. The cellular function of WRN is sti ll unclear, but on the basis of the cellular phenotypes of WS and of RecQ y east mutants, its possible role in controlling recombination and/or in main tenance of genomic integrity during S-phase has been envisaged. With the us e of two drugs, camptothecin and hydroxyurea, which produce replication-ass ociated DNA damage and/or inhibit replication fork progression, we find tha t WS cells have a slower rate of repair associated with DNA damage induced in the S-phase and a reduced induction of RAD51 foci. As a consequence, WS cells undergo apoptotic cell death more than normal cells, even if they arr est and resume DNA synthesis at an apparently normal rate. Furthermore, we report that WS cells show a higher background level of DNA strand breaks an d an elevated spontaneous induction of RAD51 foci. Our findings support,the hypothesis that WRN could be involved in the correct resolution of recombi national intermediates that arise from replication arrest due to either DNA damage or replication fork collapse.