Repair of Oxidative DNA Damage and Aging

Central Role of AP-Endonuclease
  • Sankar Mitra
  • Tadahide Izumi
  • Istvan Boldogh
  • Chilakamarti V. Ramana
  • Ching-Chyuan Hsieh
  • Hiroshi Saito
  • Julie Lock
  • John Papaconstantinou
Chapter
Part of the NATO ASI Series book series (NSSA, volume 302)

Abstract

Reactive oxygen species (ROS) generate many types of damage in cellular genomes, including base lesions, base loss, and nonligatable DNA strand breaks. These lesions are repaired predominantly via the base excision repair (BER) pathway, which is initiated by the removal of damaged bases from DNA by specific DNA glycosylases. There is strong evidence for the presence of two BER pathways, named BER I and BER II, in mammalian cells. AP-endonuclease (APE) functions as an endonuclease in BER I, which is utilized when abasic (AP) sites are generated by simple DNA glycosylases. APE functions as a DNA 3’ phosphoesterase/exonuclease in the BER II pathway which is used when 3’ blocked ends are generated in DNA either by ROS or during removal of oxidized base lesions by complex DNA glycosylase/AP lyases. In addition to its central role in the BER pathways, the major human APE (hAPE-1) possesses other unrelated activities as an activator of several transcription factors, and as a Ca2+-dependent repressor of several genes including its own. APE-1 is activated transiently in human and rodent cells by a variety of sublethal levels of ROS, but not by other genotoxic agents. Similar activation was observed in the livers of mice treated with bacterial lipopolysaccharide, an ROS inducer. This effect was less pronounced in the aged (24 mo-old) than in the young (4 mo-old) animais. These results indicate complex regulation of the APE level during age-dependent stress response of mammalian cells.

Keywords

Polypeptide NADH Nash Abate Schiff 

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Copyright information

© Springer Science+Business Media New York 1999

Authors and Affiliations

  • Sankar Mitra
    • 1
  • Tadahide Izumi
    • 1
  • Istvan Boldogh
    • 1
  • Chilakamarti V. Ramana
    • 1
    • 2
  • Ching-Chyuan Hsieh
    • 1
  • Hiroshi Saito
    • 1
  • Julie Lock
    • 1
  • John Papaconstantinou
    • 1
  1. 1.Sealy Center for Molecular Science and Department of Human Biological Chemistry and GeneticsUniversity of Texas Medical BranchGalvestonUSA
  2. 2.Cleveland Clinic Research CenterClevelandUSA

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