title: Divergent cellular phenotypes of human and mouse cells lacking the Werner syndrome RecQ helicase.
abstract: Werner syndrome (WS) is a human autosomal recessive genetic instability and cancer predisposition syndrome with features of premature aging. Several genetically determined mouse models of WS have been generated, however, none develops features of premature aging or an elevated risk of neoplasia unless additional genetic perturbations are introduced. In order to determine whether differences in cellular phenotype could explain the discrepant phenotypes of Wrn-/- mice and WRN-deficient humans, we compared the cellular phenotype of newly derived Wrn-/- mouse primary fibroblasts with previous analyses of primary and transformed fibroblasts from WS patients and with newly derived, WRN-depleted human primary fibroblasts. These analyses confirmed previously reported cellular phenotypes of WRN-mutant and WRN-deficient human fibroblasts, and demonstrated that the human WRN-deficient cellular phenotype can be detected in cells grown in 5% or in 20% oxygen. In contrast, we did not identify prominent cellular phenotypes present in WRN-deficient human cells in Wrn-/- mouse fibroblasts. Our results indicate that human and mouse fibroblasts have different functional requirements for WRN protein, and that the absence of a strong cellular phenotype may in part explain the failure of Wrn-/- mice to develop an organismal phenotype resembling Werner syndrome.
authors.affiliation: Department of Genome Sciences, University of Washington, Seattle, WA 98195, USA.
authors.forename: Kiranjit K
authors.initials: KK
authors.lastname: Dhillon
authors.forename: Julia M
authors.initials: JM
authors.lastname: Sidorova
authors.forename: Tina M
authors.initials: TM
authors.lastname: Albertson
authors.forename: Judith B
authors.initials: JB
authors.lastname: Anderson
authors.forename: Warren C
authors.initials: WC
authors.lastname: Ladiges
authors.forename: Peter S
authors.initials: PS
authors.lastname: Rabinovitch
authors.forename: Bradley D
authors.initials: BD
authors.lastname: Preston
authors.forename: Raymond J
authors.initials: RJ
authors.lastname: Monnat
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D004249:DNA Damage; D005090:Exodeoxyribonucleases / Q000172:deficiency / Q000378:metabolism*; D006657:Histones / Q000378:metabolism; D006801:Humans; D008136:Longevity; D051379:Mice; D018345:Mice, Knockout; D009369:Neoplasms / Q000201:enzymology / Q000235:genetics; D010100:Oxygen / Q000378:metabolism; D010641:Phenotype; D053484:RecQ Helicases / Q000172:deficiency / Q000378:metabolism*; D014898:Werner Syndrome / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: C468783:H2AX protein, human; D006657:Histones; C475961:gamma-H2AX protein, mouse; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; C499253:Wrn protein, mouse; D010100:Oxygen