title: Essential role for mammalian apurinic/apyrimidinic (AP) endonuclease Ape1/Ref-1 in telomere maintenance.
abstract: The major mammalian apurinic/apyrimidinic endonuclease Ape1 is a multifunctional protein operating in protection of cells from oxidative stress via its DNA repair, redox, and transcription regulatory activities. The importance of Ape1 has been marked by previous work demonstrating its requirement for viability in mammalian cells. However, beyond a requirement for Ape1-dependent DNA repair activity, deeper molecular mechanisms of the fundamental role of Ape1 in cell survival have not been defined. Here, we report that Ape1 is an essential factor stabilizing telomeric DNA, and its deficiency is associated with telomere dysfunction and segregation defects in immortalized cells maintaining telomeres by either the alternative lengthening of telomeres pathway (U2OS) or telomerase expression (BJ-hTERT), or in normal human fibroblasts (IMR90). Through the expression of Ape1 derivatives with site-specific changes, we found that the DNA repair and N-terminal acetylation domains are required for the Ape1 function at telomeres. Ape1 associates with telomere proteins in U2OS cells, and Ape1 depletion causes dissociation of TRF2 protein from telomeres. Consistent with this effect, we also observed that Ape1 depletion caused telomere shortening in both BJ-hTERT and in HeLa cells. Thus, our study describes a unique and unpredicted role for Ape1 in telomere protection, providing a direct link between base excision DNA repair activities and telomere metabolism.
authors.affiliation: Molecular Neuro-Oncology Research Unit, Department of Pediatrics and Adolescent Medicine and Institute of Neurology, Medical University of Vienna, A-1090 Vienna, Austria.
authors.forename: Sibylle
authors.initials: S
authors.lastname: Madlener
authors.forename: Thomas
authors.initials: T
authors.lastname: Ströbel
authors.forename: Sarah
authors.initials: S
authors.lastname: Vose
authors.forename: Okay
authors.initials: O
authors.lastname: Saydam
authors.forename: Brendan D
authors.initials: BD
authors.lastname: Price
authors.forename: Bruce
authors.initials: B
authors.lastname: Demple
authors.forename: Nurten
authors.initials: N
authors.lastname: Saydam
mesh_terms: D015153:Blotting, Western; D045744:Cell Line, Tumor; D047369:Chromatin Immunoprecipitation; D017931:DNA Primers / Q000235:genetics; D004260:DNA Repair / Q000502:physiology*; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase / Q000235:genetics / Q000378:metabolism*; D005455:Fluorescent Antibody Technique; D006801:Humans; D047468:Immunoprecipitation; D017404:In Situ Hybridization, Fluorescence; D019098:Telomerase / Q000378:metabolism; D059505:Telomere Homeostasis / Q000235:genetics* / Q000502:physiology
chemical_list: D017931:DNA Primers; D019098:Telomerase; C085108:APEX1 protein, human; D043603:DNA-(Apurinic or Apyrimidinic Site) Lyase
keywords: chromosome stability; endogenous DNA damage; genome stability