title: The Werner syndrome helicase protein is required for cell proliferation, immortalization, and tumorigenesis in Scaffold attachment factor B1 deficient mice.
abstract: Werner syndrome (WS) is a rare disorder characterized by the premature onset of several pathologies associated with aging. The gene responsible for WS codes for a RecQ-type DNA helicase and is believed to be involved in different aspects of DNA repair, replication, and transcription. We recently identified the Scaffold attachment factor B1 (SAFB1) as a potential interactants in human cells. SAFB1 is a multifunctional protein that binds both nucleic acids and is involved in the attachment of chromatin to the nuclear matrix, transcription, and stress response. Mice lacking SAFB1 exhibit developmental abnormalities in their lungs, high incidence of perinatal lethality, and adults develop different types of tumors. Mouse embryonic fibroblasts from Safb1-null animals are immortalized in culture. In this study, mice with a mutation in the helicase domain of the Wrn gene were crossed to Safb1-null mice. Double homozygous mutant mice exhibited increased apoptosis, a lower cell proliferation rate in their lungs and a higher incidence of perinatal death compared to Safb1-null mice. Few double homozygous mutants survived weaning and died before the age of six months. Finally, mouse embryonic fibroblasts lacking a functional Wrn helicase inhibited the immortalization of Safb1-null cells. These results indicate that an intact Wrn protein is required for immortalization and tumorigenesis in Safb1-null mice.
authors.affiliation: Centre de Recherche en Cancérologie de l'Université Laval, Hôpital Hôtel‐Dieu de Québec, Québec City, Canada.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lachapelle
authors.forename: Steffi
authors.initials: S
authors.lastname: Oesterreich
authors.forename: Michel
authors.initials: M
authors.lastname: Lebel
mesh_terms: D000818:Animals; D017209:Apoptosis; D049109:Cell Proliferation; D002470:Cell Survival; D053903:DNA Breaks, Double-Stranded; D004268:DNA-Binding Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D005090:Exodeoxyribonucleases / Q000502:physiology; D005260:Female; D057809:HEK293 Cells; D006720:Homozygote; D006801:Humans; D008136:Longevity; D008168:Lung / Q000473:pathology; D008297:Male; D036961:Matrix Attachment Region Binding Proteins / Q000502:physiology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009374:Neoplasms, Experimental / Q000209:etiology; D034521:Nuclear Matrix-Associated Proteins / Q000502:physiology; D011247:Pregnancy; D051745:Protein Kinase C-delta / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D053484:RecQ Helicases / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D011960:Receptors, Estrogen / Q000502:physiology; D014898:Werner Syndrome / Q000235:genetics / Q000473:pathology / Q000503:physiopathology; D000071657:Werner Syndrome Helicase; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; D036961:Matrix Attachment Region Binding Proteins; D034521:Nuclear Matrix-Associated Proteins; D016601:RNA-Binding Proteins; D011960:Receptors, Estrogen; C109132:SAFB protein, human; C500609:scaffold attachment factor B1, mouse; D051745:Protein Kinase C-delta; D048051:p38 Mitogen-Activated Protein Kinases; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse