Functional role of the Werner syndrome RecQ helicase in human fibroblasts.
Werner syndrome is an autosomal recessive human genetic instability and cancer predisposition syndrome that also has features of premature aging. We focused on two questions related to Werner syndrome protein (WRN) function in human fibroblasts: Do WRN-deficient fibroblasts have a consistent cellular phenotype? What role does WRN play in the recovery from replication arrest? We identified consistent cell proliferation and DNA damage sensitivity defects in both primary and SV40-transformed fibroblasts from different Werner syndrome patients, and showed that these defects could be revealed by acute depletion of WRN protein. Mechanistic analysis of the role of WRN in recovery from replication arrest indicated that WRN acts to repair damage resulting from replication arrest, rather than to prevent the disruption or breakage of stalled replication forks. These results identify readily quantified cell phenotypes that result from WRN loss in human fibroblasts; delineate the impact of cell transformation on the expression of these phenotypes; and define a mechanistic role for WRN in the recovery from replication arrest.
Dhillon
Kiranjit K
KK
Department of Pathology, University of Washington, Seattle, WA 98195-7705, USA.
Sidorova
Julia
J
Saintigny
Yannick
Y
Poot
Martin
M
Gollahon
Katherine
K
Rabinovitch
Peter S
PS
Monnat
Raymond J
RJ
D000970:Antineoplastic Agents / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002478:Cells, Cultured; D002945:Cisplatin / Q000494:pharmacology; D004249:DNA Damage; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000187:drug effects / Q000201:enzymology*; D006801:Humans; D010641:Phenotype; D053484:RecQ Helicases / Q000235:genetics / Q000378:metabolism*; D011995:Recombination, Genetic / Q000235:genetics; D014898:Werner Syndrome / Q000201:enzymology* / Q000235:genetics; D000071657:Werner Syndrome Helicase
D000970:Antineoplastic Agents; D005090:Exodeoxyribonucleases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D002945:Cisplatin