Defective telomere lagging strand synthesis in cells lacking WRN helicase activity.
Cells from Werner syndrome patients are characterized by slow growth rates, premature senescence, accelerated telomere shortening rates, and genome instability. The syndrome is caused by the loss of the RecQ helicase WRN, but the underlying molecular mechanism is unclear. Here we report that cells lacking WRN exhibit deletion of telomeres from single sister chromatids. Only telomeres replicated by lagging strand synthesis were affected, and prevention of loss of individual telomeres was dependent on the helicase activity of WRN. Telomere loss could be counteracted by telomerase activity. We propose that WRN is necessary for efficient replication of G-rich telomeric DNA, preventing telomere dysfunction and consequent genomic instability.
Crabbe
Laure
L
Salk Institute for Biological Studies, 10010 North Torrey Pines Road, La Jolla, CA 92037, USA.
Verdun
Ramiro E
RE
Haggblom
Candy I
CI
Karlseder
Jan
J
D000483:Alleles; D000705:Anaphase; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins; D002460:Cell Line; D002478:Cells, Cultured; D002842:Chromatids / Q000378:metabolism; D002877:Chromosomes, Human / Q000502:physiology; D004249:DNA Damage; D004265:DNA Helicases / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins; D005090:Exodeoxyribonucleases; D042822:Genomic Instability; D006367:HeLa Cells; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008957:Models, Genetic; D009154:Mutation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D053484:RecQ Helicases; D016196:S Phase; D019098:Telomerase / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D025521:Tumor Suppressor Proteins; D014898:Werner Syndrome / Q000235:genetics*; D000071657:Werner Syndrome Helicase
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D019098:Telomerase; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase