Redox regulation of the DNA repair function of the human AP endonuclease Ape1/ref-1

M. R. Kelley, S. H. Parsons

Research output: Contribution to journalArticle

84 Scopus citations

Abstract

The second enzyme in the DNA base excision repair (BER) pathway, apurinic/apyrimidinic (AP) endonuclease or Ape1, hydrolyzes the phosphodiester backbone immediately 5′ to an AP site generating a normal 3′-hydroxyl group and an abasic deoxyribose-5-phosphate, which is processed by subsequent enzymes of the BER pathway. AP sites are the most common form of DNA damage, and the persistence of AP sites in DNA results in a block to DNA replication, cytotoxic mutations, and genetic instability. Interestingly, Ape1/ref-1 is a multifunctional protein that not only is a DNA repair enzyme, but also functions as a redox factor maintaining transcription factors, such as Fos, Jun, nuclear factor-κB, PAX (paired box-containing family of genes), hypoxia inducible factor-1α (HIF-1α), HIT-1-like factor, and p53, in an active reduced state. Ape1/ref-1 has also been implicated in a number of other activities, one of which is the activation of bioreductive drugs requiring reduction for activity. In this report, we present data supporting our findings that another level of posttranslational modification of Ape1/ref-1 that clearly affects the AP endonuclease activity is the reduction or oxidation of this protein. Furthermore, we show data demonstrating that at least one of the sites involved in this redox regulation is the cysteine amino acid found at position 310, immediately adjacent to the crucial histidine residue at position 309 in the DNA repair active site. These findings suggest that the Ape1/ref-1 protein may be much more intimately regulated at the posttranslational level than initially imagined.

Original languageEnglish (US)
Pages (from-to)671-683
Number of pages13
JournalAntioxidants and Redox Signaling
Volume3
Issue number4
DOIs
StatePublished - 2001

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Molecular Biology
  • Clinical Biochemistry
  • Cell Biology

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