Intracellular trafficking and regulation of mammalian AP-endonuclease 1 (APE1), an essential DNA repair protein

Sankar Mitra, Tadahide Izumi, Istvan Boldogh, Kishor K. Bhakat, Ranajoy Chattopadhyay, Bartosz Szczesny

Research output: Contribution to journalArticle

74 Scopus citations

Abstract

AP endonuclease (APE), with dual activities as an endonuclease and a 3′ exonuclease, is a central player in repair of oxidized and alkylated bases in the genome via the base excision repair (BER) pathway. APE acts as an endonuclease in repairing AP sites generated spontaneously or after base excision during BER. It also removes the 3′ blocking groups in DNA generated directly by ROS or after AP lyase reaction. In contrast to E. coli and lower eukaryotes which express two distinct APEs of Xth and Nfo types, mammalian genomes encode only one APE, APE1, which is of the Xth type. However, while the APEs together are dispensable in the bacteria and simple eukaryotes, APE1 is essential for mammalian cells. We have shown that apoptosis of mouse embryo fibroblasts triggered by APE1 inactivation can be prevented by ectopic expression of repair competent but not repair-defective APE1. The mitochondrial APE (mtAPE) is an N-terminal truncation product of APE1. A significant fraction of APE1 is cytosolic, and oxidative stress induces its nuclear and mitochondrial translocation. Such age-dependent increase in APE activity in the nucleus and mitochondria is consistent with the hypothesis that aging is associated with chronic oxidative stress.

Original languageEnglish (US)
Pages (from-to)461-469
Number of pages9
JournalDNA Repair
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2007

Keywords

  • Age-dependent repair activity
  • Mitochondrial APE
  • Nuclear export signal
  • Spontaneous AP sites

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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