title: Targeted inhibition of WRN helicase, replication stress and cancer.
abstract: WRN helicase has several roles in genome maintenance, such as replication, base excision repair, recombination, DNA damage response and transcription. These processes are often found upregulated in human cancers, many of which display increased levels of WRN. Therefore, directed inhibition of this RecQ helicase could be beneficial to selective cancer therapy. Inhibition of WRN is feasible by the use of small-molecule inhibitors or application of RNA interference and EGS/RNase P targeting systems. Remarkably, helicase depletion leads to a severe reduction in cell viability due to mitotic catastrophe, which is triggered by replication stress induced by DNA repair failure and fork progression arrest. Moreover, we present new evidence that WRN depletion results in early changes of RNA polymerase III and RNase P activities, thereby implicating chromatin-associated tRNA enzymes in WRN-related stress response. Combined with the recently discovered roles of RecQ helicases in cancer, current data support the targeting prospect of these genome guardians, as a means of developing clinical phases aimed at diminishing adaptive resistance to present targeted therapies.
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, IMRIC, Jerusalem 91120, Israel.
authors.forename: Natalie
authors.initials: N
authors.lastname: Orlovetskie
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, IMRIC, Jerusalem 91120, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Serruya
authors.affiliation: Institute for Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel. Electronic address: ghadaj@ekmd.huji.ac.il.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abboud-Jarrous
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, IMRIC, Jerusalem 91120, Israel. Electronic address: jarrous@md.huji.ac.il.
authors.forename: Nayef
authors.initials: N
authors.lastname: Jarrous
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use*; D004260:DNA Repair / Q000187:drug effects / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D053484:RecQ Helicases / Q000037:antagonists & inhibitors; D000071657:Werner Syndrome Helicase / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D053484:RecQ Helicases; D000071657:Werner Syndrome Helicase
keywords: DNA repair; EGS; RNase P; Replication stress; Selective cancer therapy; WRN helicase