title: Werner's syndrome protein is phosphorylated in an ATR/ATM-dependent manner following replication arrest and DNA damage induced during the S phase of the cell cycle.
abstract: Werner's syndrome (WS) is an autosomal recessive disorder, characterized at the cellular level by genomic instability in the form of variegated translocation mosaicism and extensive deletions. Individuals with WS prematurely develop multiple age-related pathologies and exhibit increased incidence of cancer. WRN, the gene defective in WS, encodes a 160-kDa protein (WRN), which has 3'-5'exonuclease, DNA helicase and DNA-dependent ATPase activities. WRN-defective cells are hypersensitive to certain genotoxic agents that cause replication arrest and/or double-strand breaks at the replication fork, suggesting a pivotal role for WRN in the protection of the integrity of the genoma during the DNA replication process. Here, we show that WRN is phosphorylated through an ATR/ATM dependent pathway in response to replication blockage. However, we provide evidence that WRN phosphorylation is not essential for its subnuclear relocalization after replication arrest. Finally, we show that WRN and ATR colocalize after replication fork arrest, suggesting that WRN and the ATR kinase collaborate to prevent genome instability during the S phase.
authors.affiliation: CNRS, UPR2169 'Genetic Instability and Cancer', Institut Gustave Roussy, France.
authors.forename: Pietro
authors.initials: P
authors.lastname: Pichierri
authors.forename: Filippo
authors.initials: F
authors.lastname: Rosselli
authors.forename: Annapaola
authors.initials: A
authors.lastname: Franchitto
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D002166:Camptothecin / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000378:metabolism*; D022003:Cell Nucleus Structures / Q000378:metabolism; D002478:Cells, Cultured; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology*; D004265:DNA Helicases / Q000378:metabolism*; D004261:DNA Replication / Q000187:drug effects; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005090:Exodeoxyribonucleases; D005347:Fibroblasts / Q000187:drug effects; D006801:Humans; D006918:Hydroxyurea / Q000494:pharmacology; D008214:Lymphocytes / Q000187:drug effects / Q000473:pathology; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D053484:RecQ Helicases; D016196:S Phase / Q000235:genetics*; D025521:Tumor Suppressor Proteins; D014898:Werner Syndrome / Q000473:pathology; D000071657:Werner Syndrome Helicase
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D005090:Exodeoxyribonucleases; D004265:DNA Helicases; D053484:RecQ Helicases; C098785:WRN protein, human; D000071657:Werner Syndrome Helicase; D006918:Hydroxyurea; D002166:Camptothecin