Werner syndrome protein prevents DNA breaks upon chromatin structure alteration.
Werner syndrome is a rare disorder characterized by genome instability and the premature onset of several pathologies associated with aging. The gene responsible for Werner syndrome codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. The human Werner protein (WRN) translocates from nucleoli to the nucleoplasm upon DNA damage. Here, for the first time we show WRN translocation following treatment with chloroquine (CHL) or trichostatin A (TSA), agents that alter chromatin structure without producing DNA breaks. In contrast to normal cells, WRN deficient human and murine cells incurred extensive DNA breaks upon CHL or TSA treatment, indicating a functional role for WRN in the proper response to these agents. Cells deficient for another RecQ-type helicase, Bloom syndrome, were not sensitive to these agents. WRN is known from in vitro studies to bind and stimulate the activity of topoisomerase I (Topol). CHL enhanced the association between WRN and Topol, suggesting that topological stress elicits a requirement for the stimulation of Topol by WRN. Supporting this idea, overexpression of Topol reduced CHL and TSA-induced DNA breaks in WRN null cells. We thus describe a novel function for WRN in ensuring genome stability to act in concert with Topol to prevent DNA breaks, following alterations in chromatin topology.
Turaga
Ramachander V N
RV
Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel-Dieu de Québec, Québec, Canada.
Massip
Laurent
L
Chavez
Alejandro
A
Johnson
F Brad
FB
Lebel
Michel
M
D000818:Animals; D001816:Bloom Syndrome; D002460:Cell Line; D045744:Cell Line, Tumor; D016922:Cellular Senescence; D002738:Chloroquine / Q000494:pharmacology; D002843:Chromatin / Q000187:drug effects* / Q000648:ultrastructure; D053960:DNA Breaks; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases; D042822:Genomic Instability; D006801:Humans; D006877:Hydroxamic Acids / Q000494:pharmacology; D051379:Mice; D018384:Oxidative Stress; D017382:Reactive Oxygen Species / Q000378:metabolism; D053484:RecQ Helicases / Q000172:deficiency / Q000378:metabolism*; D059004:Topoisomerase I Inhibitors; D014162:Transfection; D014898:Werner Syndrome; D000071657:Werner Syndrome Helicase
D002843:Chromatin; D004268:DNA-Binding Proteins; D006877:Hydroxamic Acids; D017382:Reactive Oxygen Species; D059004:Topoisomerase I Inhibitors; C012589:trichostatin A; D002738:Chloroquine; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D004264:DNA Topoisomerases, Type I