title: Telomeric DNA induces p53-dependent reactive oxygen species and protects against oxidative damage.
abstract: BACKGROUND
  Reactive oxygen species (ROS) are generated by cellular metabolism as well as by exogenous agents. While ROS can promote cellular senescence, they can also act as signaling molecules for processes that do not lead to senescence. Telomere homolog oligonucleotides (T-oligos) induce adaptive DNA damage responses including increased DNA repair capacity and these effects are mediated, at least in part, through p53.
  
  
  OBJECTIVE
  Studies were undertaken to determine whether such p53-mediated protective responses include enhanced antioxidant defenses.
  
  
  METHODS
  Normal human fibroblasts as well as R2F fibroblasts expressing wild type or dominant negative p53 were treated with an 11-base T-oligo, a complementary control oligo or diluents alone and then examined by western blot analysis, immunofluorescence microscopy and various biochemical assays.
  
  
  RESULTS
  We now report that T-oligo increases the level of the antioxidant enzymes superoxide dismutase 1 and 2 and protects cells from oxidative damage; and that telomere-based gammaH2AX (DNA damage) foci that form in response to T-oligos contain phosphorylated ATM and Chk2, proteins known to activate p53 and to mediate cell cycle arrest in response to oxidative stress. Further, T-oligo increases cellular ROS levels via a p53-dependent pathway, and these increases are abrogated by the NAD(P)H oxidase inhibitor diphenyliodonium chloride.
  
  
  CONCLUSIONS
  These results suggest the existence of innate telomere-based protective responses that act to reduce oxidative damage to cells. T-oligo treatment induces the same responses and offers a new model for studying intracellular ROS signaling and the relationships between DNA damage, ROS, oxidative stress, and cellular defense mechanisms.
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, MA 02118, USA.
authors.forename: Margaret S
authors.initials: MS
authors.lastname: Lee
authors.forename: Mina
authors.initials: M
authors.lastname: Yaar
authors.forename: Mark S
authors.initials: MS
authors.lastname: Eller
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Rünger
authors.forename: Ying
authors.initials: Y
authors.lastname: Gao
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Gilchrest
mesh_terms: D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000378:metabolism; D002460:Cell Line; D064447:Checkpoint Kinase 2; D004247:DNA / Q000378:metabolism; D004249:DNA Damage / Q000187:drug effects / Q000502:physiology; D004260:DNA Repair / Q000187:drug effects / Q000502:physiology; D004268:DNA-Binding Proteins / Q000378:metabolism; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006657:Histones / Q000378:metabolism; D006801:Humans; D019255:NADPH Oxidases / Q000378:metabolism; D009841:Oligonucleotides / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000819:agonists / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016615:Telomere; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; D009841:Oligonucleotides; D017382:Reactive Oxygen Species; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D004247:DNA; D019255:NADPH Oxidases; D064447:Checkpoint Kinase 2; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases