title: Targeted inhibition of WRN helicase by external guide sequence and RNase P RNA.
abstract: Human WRN, a RecQ helicase encoded by the Werner syndrome gene, is implicated in genome maintenance, including replication, recombination, excision repair and DNA damage response. These genetic processes and expression of WRN are concomitantly upregulated in many types of cancers. Therefore, targeted destruction of this helicase could be useful for elimination of cancer cells. Here, we provide a proof of concept for applying the external guide sequence (EGS) approach in directing an RNase P RNA to efficiently cleave the WRN mRNA in cultured human cell lines, thus abolishing translation and activity of this distinctive 3'-5' DNA helicase-nuclease. Remarkably, EGS-directed knockdown of WRN leads to severe inhibition of cell viability. Hence, further assessment of this targeting system could be beneficial for selective cancer therapies, particularly in the light of the recent improvements introduced into EGSs.
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel.
authors.forename: Anna
authors.initials: A
authors.lastname: Hitrik
authors.affiliation: Institute for Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel.
authors.forename: Ghada
authors.initials: G
authors.lastname: Abboud-Jarrous
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, 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, Jerusalem 91120, Israel.
authors.forename: Raphael
authors.initials: R
authors.lastname: Serruya
authors.affiliation: Department of Microbiology and Molecular Genetics, The Hebrew University-Hadassah Medical School, Jerusalem 91120, Israel; Institute for Dental Sciences, The Hebrew University-Hadassah School of Dental Medicine, Jerusalem 91120, Israel. Electronic address: jarrous@md.huji.ac.il.
authors.forename: Nayef
authors.initials: N
authors.lastname: Jarrous
mesh_terms: D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004261:DNA Replication / Q000235:genetics; D005090:Exodeoxyribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics*; D015894:Genome, Human; D042822:Genomic Instability / Q000235:genetics; D006801:Humans; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D053484:RecQ Helicases / Q000037:antagonists & inhibitors / Q000235:genetics*; D043262:Ribonuclease P / Q000235:genetics*; D014898:Werner Syndrome / Q000235:genetics* / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: D012333:RNA, Messenger; D005090:Exodeoxyribonucleases; D043262:Ribonuclease P; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase
keywords: External guide sequence; RNase P RNA; WRN helicase, selective cancer therapy; Werner syndrome