Defective telomere lagging strand synthesis in cells lacking WRN helicase activity

Science. 2004 Dec 10;306(5703):1951-3. doi: 10.1126/science.1103619.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alleles
  • Anaphase
  • Ataxia Telangiectasia Mutated Proteins
  • Cell Cycle Proteins
  • Cell Line
  • Cells, Cultured
  • Chromatids / metabolism
  • Chromosomes, Human / physiology
  • DNA Damage
  • DNA Helicases / genetics
  • DNA Helicases / metabolism*
  • DNA-Binding Proteins
  • Exodeoxyribonucleases
  • Genomic Instability
  • HeLa Cells
  • Humans
  • In Situ Hybridization, Fluorescence
  • Models, Genetic
  • Mutation
  • Protein-Serine-Threonine Kinases / metabolism
  • RecQ Helicases
  • S Phase
  • Telomerase / metabolism
  • Telomere / metabolism*
  • Tumor Suppressor Proteins
  • Werner Syndrome / genetics*
  • Werner Syndrome Helicase

Substances

  • Cell Cycle Proteins
  • DNA-Binding Proteins
  • Tumor Suppressor Proteins
  • ATM protein, human
  • Ataxia Telangiectasia Mutated Proteins
  • Protein-Serine-Threonine Kinases
  • Telomerase
  • Exodeoxyribonucleases
  • DNA Helicases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase